Efficient sulfonation of 1-phenylsulfonyl-1H-pyrroles and 1-phenylsulfonyl-1H-indoles using chlorosulfonic acid in acetonitrile

Article abstract of DOI:10.1016/j.tet.2005.11.062

The sulfonation of various 1-phenylsulfonyl-1H-pyrroles and 1-phenylsulfonyl-1H-indoles using chlorosulfonic acid in acetonitrile has been studied, leading to the development of a clean and operationally simple protocol allowing direct synthesis of the corresponding 1-phenylsulfonyl-1H-pyrrole-3- sulfonyl chlorides and 1-phenylsulfonyl-1H-indole-3-sulfonyl chlorides, respectively, both of which may be easily converted to various sulfonamide derivatives by treatment with nitrogen nucleophiles. Efficient and selective removal of the phenylsulfonyl- or tosyl groups in the sulfonamide series may be achieved under mild conditions.

Full text of DOI:10.1016/j.tet.2005.11.062

Tetrahedron 62 (2006) 1699–1707
Efficient sulfonation of 1-phenylsulfonyl-1H-pyrroles and
1-phenylsulfonyl-1H-indoles using chlorosulfonic acid
in acetonitrile
a
a
a
Tomasz Janosik,a, Hamid Shirani, Niklas Wahlstrom, Ilham Malky,
*
¨
Birgitta Stenslandb and Jan Bergmana,c,
*
aUnit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park,
SE-141 57, Huddinge, Sweden
¨ ¨
Preformulation and Biopharmaceutics, Solid State Analysis AstraZeneca PAR & D/SBBG B341:3, SE-151 85 Sodertalje, Sweden
b
c
¨
¨
Sodertorn University College, SE-141 04 Huddinge, Sweden
Received 1 September 2005; revised 3 November 2005; accepted 24 November 2005
Available online 20 December 2005
Abstract—The sulfonation of various 1-phenylsulfonyl-1H-pyrroles and 1-phenylsulfonyl-1H-indoles using chlorosulfonic acid in
acetonitrile has been studied, leading to the development of a clean and operationally simple protocol allowing direct synthesis of the
corresponding 1-phenylsulfonyl-1H-pyrrole-3-sulfonyl chlorides and 1-phenylsulfonyl-1H-indole-3-sulfonyl chlorides, respectively, both of
which may be easily converted to various sulfonamide derivatives by treatment with nitrogen nucleophiles. Efficient and selective removal of
the phenylsulfonyl- or tosyl groups in the sulfonamide series may be achieved under mild conditions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
indoles possessing alkyl substituents with pyridinium-
1-sulfonate in refluxing pyridine gave the expected
pyridinium indole-3-sulfonates in good yields.4 Moreover,
four different indole-3-sulfonyl chlorides (1) have been
obtained by sulfonation of the corresponding nitroindoles
with chlorosulfonic acid in anhydrous chloroform in the
presence of sodium sulfate.5 The latter example demon-
strates that the presence of strong electron-withdrawing
substituents is necessary in order to access the desired
products if the process is performed in acidic media. Similar
structural requirements are valid for pyrroles, as a series of
ethyl pyrrole-2-carboxylates having various substituents
at the pyrrole nitrogen, for example, 2, were prepared by
sulfonation in neat chlorosulfonic acid.6 In contrast
to previous claims that pyrrole undergoes sulfonation
with sulfur trioxide pyridine complex to afford pyridinium
1H-pyrrole-2-sulfonate,7 it was recently shown that this
reaction gives instead the corresponding C-3-sulfonated
product. Thus, sulfonation of pyrrole with sulfur trioxide
pyridine complex followed by treatment with Na2CO3 gave
the salt 3, which could in turn be converted to the sulfonyl
chloride 4 upon treatment with PCl5. The position of the
substitution in 3 was elucidated from NOESY data, and
further corroborated by an X-ray crystallographic study of a
bicyclic sulfonamide derived from 4 (Fig. 1).8
Sulfonation of aromatic compounds is a process of great
industrial importance due to the availability and low cost of
the reagents (i.e., H2SO4, HOSO2Cl, SO3, or its pyridine
complex), the relatively simple technology required for
these types of transformations, and perhaps most impor-
tantly, the broad applicability of the resulting products, for
instance sulfonic acids and sulfonyl chlorides. Conse-
quently, sulfonation reactions have been studied extensively
over the years, leading to the syntheses of a multitude of
various aromatic sulfonyl derivatives.1,2 The mechanistic
aspects of sulfonation and related reactions have also been
investigated in considerable detail.2 Despite the fact that
efficient procedures for the sulfonation of a number of
different heterocycles are known,3 only a few examples of
sulfonation reactions involving pyrroles or indoles have
been described. Both indole and pyrrole are electron rich
heterocyles, which dimerize or polymerize readily under
acidic conditions, thereby severely limiting the choice of
reagents and substrates. For example, treatment of various
Keywords: Pyrroles; Indoles; Sulfonation; Chlorosulfonic acid.
*
Corresponding authors. Tel.: C46 8 6089206; fax: C46 8 6081501;
e-mail addresses: toja@cnt.ki.se; jabe@cnt.ki.se
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.062

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T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
performed on the 1-phenylsulfonyl-1H-pyrroles 7a–b14a in
O
S
O
S
O
O
neat chlorosulfonic acid employing a procedure previously
used for chlorosulfonation of some related electron deficient
pyrroles6 led to severe decomposition of the starting
materials, the reactions were instead conducted in the
presence of acetonitrile as the solvent. Using this reagent–
solvent combination, clean conversion of 7a–b to the
desired 1-phenylsulfonyl-1H-pyrrole-3-sulfonyl chlorides
8a–b took place (Scheme 1). Although the yields of 8a
and 8b (46 and 37%, respectively) were only moderate, this
route is very attractive because of the operational simplicity
and the high purity even of the crude products. All side
products are conveniently removed during aqueous workup.
An excess of chorosulfonic acid must be used in order to
effect efficient conversion to the desired sulfonyl chlorides,
since it is known that treatment of, for example, benzene
with equimolar amounts of chlorosulfonic acid gives
benzenesulfonic acid, which is then in turn converted to
benzenesulfonyl chloride upon treatment with an excess of
the sulfonating agent in an equilibrium process.15 Next, we
turned our attention to even more electron deficient pyrroles
such as 7c–d. The standard procedures for the N-protection
of pyrrole using phenylsulfonyl chlorides, which are usually
conducted in the presence of strong inorganic bases such as
NaOH16 or KOH,17 did not prove to be applicable for the
synthesis of 7c–d due to rapid decomposition of the
products upon exposure to the strongly basic conditions
(complex tarry mixtures were obtained). The alternative
methods relying on treatment of pyrrole with potassium in
refluxing THF, and subsequent introduction of 4-nitro-
benzenesulfonyl chloride,14a or the reaction of 4-nitro-
benzenesulfonamide with 2,5-dimethoxytetrahydrofuran,14b
have been reported to give 1-(4-nitrophenyl)sulfonyl-1H-
pyrrole (7c) in yields of only 26 and 46%, respectively. On
the other hand, treatment of pyrrole with butyllithium in
THF, followed by introduction of the appropriate sulfonyl
chlorides, enabled clean and high-yielding syntheses of the
known pyrroles 7a–c,14a as well as the new compound 7d.
As anticipated, the pyrroles 7c–d gave even better results
during sulfonation, affording the corresponding sulfonyl
chlorides 8c–d in 56 and 58% yield, respectively, thus also
supporting our expectation that the presence of strongly
electron-withdrawing groups in the phenylsulfonyl part of
the pyrroles 7 would provide higher yields of the sulfonyl
chlorides 8. In an additional experiment, the sulfonyl
Cl
Cl
O2N
CH3
C2H5O2C
N
N
H
CH3
2
1
O
S
O
O
O
ONa
S
Cl
N
N
H
H
3
4
Figure 1.
Indoles possessing sulfone- or sulfonamide functionalities
at C-3 have attracted considerable interest in medicinal
chemistry. Thus, for example, L-737,126 (5) has been
investigated as a inhibitor of HIV-1 reverse trancriptase,9
while a series of closely related sulfones have been shown to
possess activity against resistant HIV-1 mutants.10 Very
recently, short peptide derivatives of L-737,126 (5) have
been demonstrated to exhibit in vitro activity against HIV-1
wild type and mutants possessing non-nucleoside reverse
transcriptase inhibitor resistance.11 The platelet-activating
factor antagonist 6 was prepared via an indole-3-sulfonyl
chloride, which was obtained from the corresponding
N-protected indole involving bromination at C-3, followed
by halogen–lithium exchange, treatment of the organo-
metallic intermediate with SO2, and subsequent chlorination
with NCS (Fig. 2).12
O
O
Cl
S
CONH2
N
H
5
N
H3C
O
S
N
O
N
N
F
N
O
N(CH3)2
O
O
S
Cl
6
Figure 2.
N
S
N
S
i, ii
iii
O
O
O
O
2. Results and discussion
N
H
In order to evaluate the scope and limitations of
chlorosulfonation of electron deficient indoles and pyrroles,
a series of phenylsulfonyl-protected substrates were
selected. Both 1-phenylsulfonyl-1H-indoles and 1-phenyl-
sulfonyl-1H-pyrroles can be readily prepared, are stable
towards acidic media, and the N-protecting group can be
removed conveniently under various conditions.13 Surpris-
ingly enough, the reactivity of 1-phenylsulfonyl-1H-indoles
and 1-phenylsulfonyl-1H-pyrroles towards sulfonating
agents has never been studied. Since our initial experiments
R
R
7a R = H (98%)
8a R = H (46%)
7b R = CH3 (93%)
7c R = NO2 (92%)
7d R = CF3 (93%)
8b R = CH3 (37%)
8c R = NO2 (56%)
8d R = CF3 (58%)
Scheme 1. Reagents and conditions: (i) BuLi, THF, K78 8C to rt, 1 h;
(ii) RC6H4SO2Cl, K78 8C to rt, 15–20 h; (iii) HOSO2Cl, CH3CN, rt,
70–75.5 h.

T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
1701
chloride 8c could also be obtained in comparable yield when
7c and chlorosulfonic acid were heated at reflux in
acetonitrile for 1.5 h, but the product contained a few
percent of impurities (not identified), and the procedure
performed at rt is therefore the method of choice. An X-ray
crystallographic study of 8a confirmed the expected
functionalization at C-3 (Fig. 3),18 which is in analogy
with, for example, the regioselective C-3 acylation of
1-phenylsulfonyl-1H-pyrroles mediated by AlCl3.16b,19
Thus, the position of sulfonation is the same when using
our procedure, as during sulfonation of pyrrole itself with
sulfur trioxide pyridine complex in pyridine.8 It is also
interesting to note that the crystal structure of 8a displays
very similar geometry around the N-phenylsulfonyl unit as
noted previously in several 1-phenylsulfonyl-1H-pyrroles
and -indoles.20
Based on the observations made during the studies on the
reactivity of 1-phenylsulfonyl-1H-pyrroles towards chloro-
sulfonic acid in acetonitrile, we wished to extend the scope
of our method to indoles. A series of 1-phenylsulfonyl-1H-
indoles was therefore subjected to similar reaction
conditions. For instance, the readily available 1-phenyl-
sulfonyl-1H-indole (9a)16a,21 and 1-(p-toluenesulfonyl)-1H-
indole (9b)16a underwent clean conversion to the sulfonyl
chlorides 10a and 10b, respectively, upon treatment with
3 equiv of chlorosulfonic acid in acetonitrile (Scheme 2).
The yields of these transformations were, just as expected,
considerably higher than in the pyrrole series because the
indoles 9a–b are less electron rich heterocycles than the
corresponding pyrroles, and are therefore also less likely to
participate in side-reactions. Acceptable results can also be
obtained by performing the reactions for shorter periods of
time (48 h), which generally only leads to somewhat lower
yields. Further deactivation of the indole nucleus leads, in
similarity to the reactivity trend observed in the pyrrole
series, to even more efficient chlorosulfonation, as
illustrated by the syntheses of the halogenated indole-3-
sulfonyl chlorides 10c–e upon exposure of the indoles 9c,22
9e,23 and 6-chloro-1-phenylsulfonyl-1H-indole (9d) to
approximately 4 equiv of chlorosulfonic acid. On the other
hand, the considerably more electron rich 5-methoxy-1-
phenylsulfonyl-1H-indole24 gave only a very low yield
(w5%) of 5-methoxy-1-phenylsulfonyl-1H-indole-3-sulfo-
nyl chloride in impure form under similar conditions, even
when the reaction was initially performed at 0 8C, followed
by slow warming to rt overnight. Attempted sulfonation
of the somewhat more deactivated 5-methoxy-1-(4-nitro-
phenyl)sulfonyl-1H-indole25 gave similar results.
Obviously, the presence of electron releasing groups on
the six-membered ring of the indole leads to extensive side
reactions, and very little of the desired 3-sulfonated
products are formed.
Figure 3. The molecular structure of compound 8a, showing the atom
labelling used in the crystal structure refinement.18
O
O
S
Cl
X
X
N
N
i
With substantial amounts of sulfonyl chlorides 8a–d and
10a–e in hand, studies of the reactivity and synthetic
applicability of these compounds were initiated. For that
purpose, indole-3-sulfonyl chlorides 10a–b were chosen as
the substrates and subjected to reactions with selected
nitrogen nucleophiles (Scheme 3). Both compounds 10a–b
were cleanly converted to the imidazole derivatives 11a–b
upon treatment with imidazole in CH2Cl2. Likewise,
exposure of 10a to an excess of morpholine gave the
sulfonamide 12 in excellent yield. As anticipated, cleavage
of the phenylsulfonyl group of 12 was carried out
conveniently and selectively employing potassium carbonate
in aqueous methanol, providing the sulfonamide 13.
O
S O
O
S O
R
R
9a R = H, X = H
10a R = H, X = H (79%)
10b R = CH3, X = H (72%)
10c R = H, X = 6-Br (88%)
10d R = H, X = 6-Cl (89%)
10e R = H, X = 5-F (100%)
9b R = CH3, X = H
9c R = H, X = 6-Br
9d R = H, X = 6-Cl
9e R = H, X = 5-F
Scheme 2. Reagents and conditions: (i) HOSO2Cl, CH3CN, 0 8C to rt (for
10a–b) or rt (for 10c–e), 66–75.5 h.
O
S
O
O
O
O
O
N
S
N
Cl
S
N
O
ii
i
N
N
R
N
R
R
12 R = SO2Ph (93%)
13 R = H (92%)
10a R = SO2Ph
10b R = Ts
11a R = SO2Ph (91%)
11b R = Ts (74%)
iii
Scheme 3. Reagents and conditions: (i) imidazole, CH2Cl2, rt; (ii) morpholine, CH2Cl2, rt; (iii) K2CO3, MeOH, H2O, rt.

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T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
O
X
O
S
X
O
O
X
S
N
N
iii
i, ii
N
H
N
R
N
H
15a R = SO2Ph, X = H (54%)
15b R = Ts, X = CO2t-Bu (46%)
16a X = H (80%)
16b X = CO2t-Bu (93%)
14a X = H
14b X = CO2t-Bu
Scheme 4. Reagents and conditions: (i) LDA, THF, K78 8C; (ii) 10a (for 14a), or 10b (for 14b), K78 8C to rt; (iii) K2CO3, MeOH, H2O, rt (for 15a), or
K2CO3, MeOH, THF, H2O, rt (for 15b).
The sulfonyl chlorides 10a–b were also used in reactions
with N-metalated derivatives of the indoles 14a and 14b26
(readily available by treatment of indole-3-carboxylic acid
with oxalyl chloride, followed by exposure of the
intermediate acid chloride to potassium tert-butoxide in
t-BuOH), affording the new sulfur-containing systems 15a
and 15b, respectively (Scheme 4). The use of LDA proved
to be crucial in this application, as attempts involving indole
and potassium tert-butoxide or BuLi gave inferior yields of
the desired product 15a, along with compound 16a,
resulting from base-induced cleavage of the protecting
group. Again, selective cleavage of the phenylsulfonyl- or
p-toluenesulfonyl protecting groups was achieved by
treatment with potassium carbonate rendering compounds
16a–b. Under these mild conditions, the sulfonyl linkage
between the indole units remained untouched, presumably
as a result of the different steric and electronic properties of
the two sulfone functionalities. A member belonging to this
class, namely 3-(1H-indole-1-sulfonyl)-7-nitro-1H-indole,
has been prepared recently by treatment of indole with
sodium hydride, followed by introduction of 7-nitro-1H-
indole-3-sulfonyl chloride,5 as an intermediate en route to
new compounds displaying affinity for the 5-HT6-
receptor.27 Attempts to use the sulfonyl chlorides 10a–b
in reactions with indolyl magnesium halides or C-metalated
indoles under a variety of different conditions failed to
produce the corresponding diindolyl sulfones.
derivatives clearly indicate that a wide variety of
sulfonamides may be generated by reactions with suitable
nitrogen nucleophiles, providing practical routes to new
heterocyclic systems with potential for pharmacological
applications, and that selective cleavage of the phenyl-
sulfonyl or p-toluenesulfonyl protecting groups takes place
under mild conditions, which tolerate the presence of
sensitive functional groups.
3. Experimental
3.1. General experimental procedures
NMR data were recorded at 300.1 MHz for 1H, and
75.5 MHz for 13C, respectively. IR spectra were acquired
on a FT-IR instrument. High-resolution mass spectra were
recorded by Nilsson, University of Lund, Sweden. The
elemental analyses were performed by Kolbe Mikroanaly-
tisches Laboratorium, Mu¨lheim an der Ruhr, Germany.
Melting points were taken on a capillary apparatus in open
capillary tubes. All reactions were performed under nitrogen
atmosphere. Acetonitrile (analytical grade) was stored over
˚
activated molecular sieves (4 A). Pyrrole was freshly
distilled prior to use. THF was distilled from sodium and
benzophenone.
3.1.1. 1-Phenylsulfonyl-1H-pyrrole (7a). BuLi (1.6 M in
hexanes, 32.6 mL, 52.2 mmol) was added to a solution
pyrrole (3.48 mL, 50 mmol) in anhydrous THF (100 mL)
at K78 8C during 20 min. After complete addition, the
mixture was stirred at K78 8C for 10 min, and was
thereafter allowed to reach rt over 1 h. After cooling to
K78 8C, a solution of benzenesulfonyl chloride (6.41 mL,
50 mmol) in anhydrous THF (12 mL) was added over
20 min at K78 8C. The resulting mixture was allowed to
slowly reach rt overnight (w18.5 h), was thereafter poured
into water (w200 mL) containing brine (w20 mL), and
extracted with CH2Cl2 (100 mL) and (3!50 mL). The
combined organic extracts were washed with water
(100 mL), followed by a mixture of water (50 mL) and
brine (50 mL), and dried over MgSO4. Removal of the
solvents in vacuo gave pure 1-phenylsulfonyl-1H-pyrrole
(7a) (10.17 g, 98%) as an off-white solid. If necessary, this
material can be crystallized from i-PrOH. Colourless plates,
mp (i-PrOH) 88–89 8C [lit.14a mp (MeOH) 89–89.5 8C].
In analogy to the indole-3-sulfonyl chlorides, the pyrrole-3-
sulfonyl chloride 8a could be efficiently converted to the
sulfonamide 17, which was in turn deprotected rendering
18 (Scheme 5), thus demonstrating the applicability of this
chemistry to the pyrrole series.
O
S
O
S
O
O
Cl
N
O
i
N
N
SO2Ph
R
8a
17 R = SO2Ph (93%)
18 R = H (83%)
ii
Scheme 5. Reagents and conditions: (i) morpholine, CH2Cl2, rt; (ii) K2CO3,
MeOH, H2O, rt.
Inconclusion,apracticalprocedureforsulfonationof1-arylsul-
fonyl-1H-pyrroles and 1-arylsulfonyl-1H-indoles with chlor-
osulfonic acid in acetonitrile has been developed. Initial
experiments probing the reactivity of the 1-arylsulfonyl-1H-
indole-3-sulfonyl chlorides and the corresponding pyrrole
3.1.2. 1-(4-Methyl-phenylsulfonyl)-1H-pyrrole (7b). This
compound was prepared according to the procedure above
using p-toluenesulfonyl chloride (9.53 g, 50 mmol)
dissolved in anhydrous THF (15 mL). Yield: 10.25 g
(93%). If necessary, this compound can be crystallized

T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
1703
from i-PrOH. Colourless plates, mp (i-PrOH) 103–103.5 8C
[lit.14a mp (MeOH) 104.5 8C].
powdered NaOH (3.13 g, 78 mmol) in CH2Cl2 (50 mL)
cooled to 0 8C were added 6-bromoindole (4.90 g, 25 mmol)
in one portion, followed by tetrabutylammonium hydro-
gensulfate (220 mg, 0.65 mmol). To this mixture was
thereafter added benzenesulfonyl chloride (4.0 mL,
31 mmol) dropwise at 0 8C during w25 min. The resulting
mixture was stirred at 0 8C for 1 h, the cooling bath was then
removed, and stirring was continued for another 2 h at rt.
The mixture was filtered through Celite, the pad was washed
with several small portions of CH2Cl2, and the combined
filtrate and washings were concentrated in vacuo. The
residue was crystallized from MeOH, which gave 9c
(5.47 g) as colourless crystals. A second crop (1.66 g) was
obtained after slow concentration of the mother liquor. The
residual mother liquors were concentrated and subjected to
column chromatography [CH2Cl2–n-hexane (2/3)] to give
more 9c (1.04 g) as a colourless crystalline solid. Overall,
8.17 g (97%) of 9c was obtained. Mp (MeOH) 100–101 8C;
IR (neat) 1367, 1174, 1134, 1125, 1093, 991, 890, 804, 753,
3.1.3. 1-(4-Nitro-phenylsulfonyl)-1H-pyrrole (7c). BuLi
(1.6 M in hexanes, 16.3 mL, 26.1 mmol) was added to a
solution pyrrole (1.74 mL, 25 mmol) in anhydrous THF
(50 mL) at K78 8C during 20 min. After complete addition,
the mixture was stirred at K78 8C for 10 min, and was
thereafter allowed to reach rt over 1 h. It was thereafter
cooled to K78 8C, and a solution of 4-nitrobenzenesulfonyl
chloride (5.54 g, 50 mmol) in anhydrous THF (15 mL) was
added over 20 min at K78 8C. The resulting mixture was
allowed to slowly reach rt overnight (w15 h), was thereafter
poured into water (w200 mL) containing brine (w20 mL),
and extracted with CH2Cl2 (4!50 mL). The combined
organic extracts were washed with water (50 mL), followed
by a mixture of water (50 mL) and brine (50 mL), and dried
over MgSO4. Evaporation of the solvents gave a brownish
crystalline residue, which was dissolved in CH2Cl2
(w50 mL) and the solution was passed through a plug of
silica gel, which was washed with several small portions of
CH2Cl2. The combined filtrate and washings were con-
centrated in vacuo to give pure 7c (5.80 g, 92%) as a
yellowish/orange crystalline solid. Crystallization of this
product from i-PrOH gave analytically pure material as
golden plates, mp (i-PrOH) 140.5–141.5 8C [lit.14a mp
(MeOH) 142–142.5 8C]; IR (neat) 1525, 1375, 1346, 1191,
1169, 1061, 865, 855, 740, 730 cmK1; 1H NMR (CDCl3) d
8.33 (d, JZ8.7 Hz, 2H), 8.02 (d, JZ8.7 Hz, 2H), 7.16 (dd,
JZ2.0, 2.0 Hz, 2H), 6.35 (dd, JZ2.0, 2.0 Hz, 2H); 13C
NMR (CDCl3) d 150.8, 144.6, 128.3, 124.8, 121.2, 115.1.
1
723, 711 cmK1; H NMR (CDCl3) d 8.19 (br, 1H), 7.89–
7.87 (m, 2H), 7.59–7.32 (m, 6H), 6.62 (d, JZ3.6 Hz, 1H);
13C NMR (CDCl3) d 138.2, 135.7, 134.3, 129.8, 129.6,
127.0, 127.0, 126.9, 122.7, 118.5, 116.8, 109.2.
3.1.6. 6-Chloro-1-phenylsulfonyl-1H-indole (9d). This
material was prepared using a modification21,24a of the
procedure described by Illi.16a To a suspension of finely
powdered NaOH (1.25 g, 31 mmol) in CH2Cl2 (20 mL)
cooled to 0 8C was added 6-chloroindole (1.52 g, 10 mmol)
in one portion, followed by tetrabutylammonium hydro-
gensulfate (88 mg, 0.26 mmol). To this mixture was
thereafter added benzenesulfonyl chloride (1.4 mL,
11 mmol) dropwise at 0 8C during w20 min. The resulting
mixture was stirred at 0 8C for 1 h, the cooling bath was then
removed, and stirring was continued for another 2 h at rt.
The mixture was filtered through Celite, the pad was washed
with several small portions of CH2Cl2, and the combined
filtrate and washings were concentrated in vacuo. The
residue was crystallized from MeOH, which gave 9d
(2.10 g) as colourless crystals. The mother liquor was
concentrated and subjected to column chromatography
[CH2Cl2–n-hexane (2/3)] to give more 9d (0.70 g) as a
colourless crystalline solid. Overall, 2.80 g (96%) of 9d was
obtained. Mp (MeOH) 98–99.5 8C; IR (neat) 1363, 1170,
3.1.4. 1-(4-Trifluoromethyl-phenylsulfonyl)-1H-pyrrole
(7d). A solution of BuLi (1.6 M in hexanes, 8.2 mL,
13.1 mmol) was added to a solution pyrrole (0.87 mL,
12.5 mmol) in anhydrous THF (25 mL) at K78 8C during
10 min. After complete addition, the mixture was stirred at
K78 8C for 10 min, and was thereafter allowed to reach rt
over 1 h. It was thereafter cooled to K78 8C, and a solution
of 4-(trifluoromethyl)benzenesulfonyl chloride (3.04 g,
12.4 mmol) in anhydrous THF (6 mL) was added over
15 min at K78 8C. The resulting mixture was allowed to
slowly reach rt overnight (w20 h), was thereafter poured
into water (w100 mL) containing brine (w20 mL), and
extracted with CH2Cl2 (4!30 mL). The combined organic
extracts were washed with water (50 mL), followed by a
mixture of water (50 mL) and brine (50 mL), and dried over
MgSO4. Evaporation of the solvents in vacuo gave pure 7d
(3.19 g, 93%) as an off-white crystalline solid. Crystal-
lization from i-PrOH gave an analytically pure sample as
colourless crystals, mp (i-PrOH) 92–93.5 8C; IR (neat)
1376, 1317, 1170, 1146, 1109, 1058, 1031, 1018, 731,
1129, 1093, 897, 865, 806, 752, 723 cmK1 1H NMR
;
(CDCl3) d 8.03 (br, 1H), 7.90–7.87 (m, 2H), 7.59–7.41 (m,
5H), 7.22–7.19 (m, 1H), 6.63 (d, JZ3.7 Hz, 1H); 13C NMR
(CDCl3) d 138.2, 135.4, 134.3, 130.9, 129.6, 129.4, 127.1,
127.0, 124.3, 122.4, 113.9, 109.1. Anal. Calcd for C14H10-
NO2SCl: C, 57.63; H, 3.45; N, 4.80. Found: C, 57.60; H,
3.42; N, 4.75.
1
715 cmK1; H NMR (CDCl3) d 7.98 (d, JZ8.6 Hz, 2H),
3.1.7. 1-Phenylsulfonyl-1H-pyrrole-3-sulfonyl chloride
(8a). To a solution of 1-phenylsulfonyl-1H-pyrrole (7a)
(2.07 g, 10 mmol) in dry CH3CN (12.5 mL) was carefully
added chlorosulfonic acid (4.0 mL, 60 mmol) at rt. An
exothermic reaction ensued, and the resulting solution was
stirred at rt for 72 h. The mixture was thereafter poured on
ice/water (w100 g), and extracted with CHCl3 (3!50 mL).
The combined organic extracts were washed with saturated
aqueous NaHCO3 (3!50 mL) [addition of small amounts
of brine (w20 mL) was sometimes necessary to prevent
formation of emulsions], brine (50 mL), and dried over
7.76 (d, JZ8.6 Hz, 2H), 7.17 (dd, JZ2.1, 2.1 Hz, 2H), 6.34
(dd, JZ2.1, 2.1 Hz, 2H); 13C NMR (CDCl3) d 142.7, 135.6
(q, JC–FZ33.2 Hz), 127.5, 126.8 (q, JC–FZ3.7 Hz), 123.1
(q, JC–FZ273.1 Hz), 121.1, 114.6. Anal. Calcd for
C11H8NO2SF3: C, 48.00; H, 2.93; N, 5.09. Found: C,
47.98; H, 2.84; N, 5.02.
3.1.5. 6-Bromo-1-phenylsulfonyl-1H-indole (9c).22 This
compound was prepared using a modification21,24a of the
procedure described by Illi.16a To a suspension of finely

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T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
MgSO4. Removal of the solvents in vacuo gave pure 9a
(1.41 g, 46%) as a colourless crystalline solid. An
analytically pure sample was obtained as colourless crystals
by crystallization from CH3CN, mp (CH3CN)
131.5–132.5 8C; IR (neat) 1378, 1363, 1188, 1176, 1149,
1084, 1050, 816, 725 cmK1; 1H NMR (CDCl3) d 7.98–7.95
(m, 2H), 7.89–7.88 (m, 1H), 7.77–7.71 (m, 1H), 7.64–7.59
(m, 2H), 7.26 (dd, JZ3.4, 2.3 Hz, 1H), 6.73 (dd, JZ3.4,
1.7 Hz, 1H); 13C NMR (CDCl3) d 137.2, 135.7, 132.2,
130.3, 127.8, 124.4, 122.5, 111.1. HRMS (EI) m/z calcd for
C10H8NO4S325Cl: 304.9583 [MC], found 304.9580. Anal.
Calcd for C10H8NO4S2Cl: C, 39.28; H, 2.64; N, 4.58.
Found: C, 39.27; H, 2.57; N, 4.49.
13C NMR (CDCl3) d 140.7, 137.3 (q, JC–FZ33.6 Hz),
132.9, 128.4, 127.6 (q, JC–FZ3.6 Hz), 124.3, 123.1 (q,
JC–FZ273.5 Hz), 122.6, 111.7. HRMS (EI) m/z calcd for
C11H7NO4S325ClF3: 372.9457 [MC], found 372.9463. Anal.
Calcd for C11H7NO4S2ClF3: C, 35.35; H, 1.89; N, 3.75.
Found: C, 35.49; H, 1.98; N, 3.71.
3.1.11. 1-Phenylsulfonyl-1H-indole-3-sulfonyl chloride
(10a). To a solution of 1-phenylsulfonyl-1H-indole (9a)21
(5.14 g, 20 mmol) in dry CH3CN (25 mL) was carefully
added chorosulfonic acid (4.0 mL, 60 mmol) at 0 8C. The
solution was allowed to reach rt over w4 h, and was
thereafter stirred at rt for 68 h. The resulting mixture was
poured into ice/water (w100 g), and extracted with CHCl3
(100 mL and 2!50 mL). The combined organic extracts
were washed with saturated aqueous NaHCO3 (2!50 mL)
[addition of small amounts of brine (w20 mL) was
sometimes necessary to prevent formation of emulsions],
brine (50 mL), and dried over MgSO4. Removal of the
solvents in vacuo gave pure 10a (5.65 g, 79%) as a pinkish
crystalline solid. An analytically pure sample was obtained
as colourless crystals by crystallization from CH3CN, mp
(CH3CN) 144–145 8C; IR (neat) 1366, 1185, 1171, 1152,
3.1.8. 1-(4-Methyl-phenylsulfonyl)-1H-pyrrole-3-sulfonyl
chloride (8b). This compound was prepared according to the
procedure above, using 1-(4-methylphenyl)sulfonyl-1H-
pyrrole (2.21 g, 10 mmol). Yield: 1.17 g (37%). Colourless
crystals, mp (CH3CN) 146.5–148 8C; IR (neat) 1382, 1367,
1191, 1171, 1155, 1084, 1081, 810 cmK1 1H NMR
;
(CDCl3) d 7.87–7.83 (m, 3H), 7.40 (d, JZ8.1 Hz, 2H),
7.23 (dd, JZ3.5, 2.4 Hz, 1H), 6.71 (dd, JZ3.5, 1.7 Hz, 1H),
2.46 (s, 3H); 13C NMR (CDCl3) d 147.3, 134.2, 132.0,
131.0, 127.9, 124.3, 122.4, 111.0, 22.0. HRMS (EI) m/z
calcd for C11H10NO4S325Cl: 318.9740 [MC], found
318.9729. Anal. Calcd for C11H10NO4S2Cl: C, 41.31; H,
3.15; N, 4.38. Found: C, 41.43; H, 3.11; N, 4.36.
1142, 1112, 1089, 942, 756, 729, 702 cmK1 1H NMR
;
(CDCl3) d 8.40 (s, 1H), 8.05–7.96 (m, 4H), 7.70–7.65 (m,
1H), 7.60–7.44 (m, 4H); 13C NMR (CDCl3) d 136.9, 135.5,
134.5, 131.2, 130.2, 127.6, 127.3, 125.8, 125.2, 123.9,
120.6, 114.0. HRMS (EI) m/z calcd for C14H10NO4S325Cl:
354.9740 [MC], found 354.9734. Anal. Calcd for C14H10-
NO4S2Cl: C, 47.26; H, 2.83; N, 3.94. Found: C, 47.26; H,
2.86; N, 3.99.
3.1.9. 1-(4-Nitro-phenylsulfonyl)-1H-pyrrole-3-sulfonyl
chloride (8c). To a suspension of 1-(4-nitrophenyl)sulfonyl-
1H-pyrrole (7c) (0.63 g, 2.5 mmol) in anhydrous CH3CN
(5 mL) was added chorosulfonic acid (2.0 mL, 30 mmol)
carefully at rt. An exothermic reaction ensued. The mixture
was stirred at rt for 70 h, was thereafter poured on ice/water
(w50 g), and was extracted with CHCl3 (3!30 mL). The
combined organic extracts were washed with saturated
aqueous NaHCO3 (3!25 mL) [addition of small amounts
of brine (w20 mL) was sometimes necessary to prevent
formation of emulsions], brine (50 mL), and dried over
MgSO4. Removal of the solvents in vacuo gave pure 8c
(0.49 g, 56%) as a colourless crystalline solid. An
analytically pure sample was obtained as fine crystals with
a yellowish tinge by crystallization from CH3CN, mp
(CH3CN) 169.5–171 8C; IR (neat) 1525, 1396, 1367, 1347,
1185, 1150, 1050, 854, 740, 733 cmK1; 1H NMR (CDCl3) d
8.46 (d, JZ9.0 Hz, 2H), 8.17 (d, JZ9.0 Hz, 2H), 7.90–7.89
(m, 1H), 7.28 (dd, JZ3.5, 2.4 Hz, 1H), 6.79 (dd, JZ3.5,
1.7 Hz, 1H); 13C NMR (CDCl3) d 151.7, 142.6, 133.3,
129.3, 125.6, 124.3, 122.6, 112.0. HRMS (EI) m/z calcd for
C10H7N2O6S325Cl: 349.9434 [MC], found 349.9438. Anal.
Calcd for C10H7N2O6S2Cl: C, 34.24; H, 2.01; N, 7.99.
Found: C, 34.30; H, 1.98; N, 8.00.
3.1.12. 1-(4-Methyl-phenylsulfonyl)-1H-indole-3-sulfonyl
chloride (10b). This material was prepared as above,
starting from 1-(4-methylphenyl)sulfonyl-1H-indole
(9b)16a (5.42 g, 20 mmol). Reaction time: 66 h. Yield:
5.34 g (72%). Pinkish crystals, mp (CH3CN) 160–161 8C;
IR (neat) 1376, 1367, 1174, 1149, 1136, 1107, 1087, 939,
1
765, 758, 709 cmK1; H NMR (CDCl3) d 8.38 (s, 1H),
8.04–8.01 (m, 1H), 7.98–7.95 (m, 1H), 7.89 (d, JZ8.5 Hz,
2H), 7.54–7.43 (m, 2H), 7.35 (d, JZ8.5 Hz, 2H), 2.40 (s,
3H); 13C NMR (CDCl3) d 147.1, 134.5, 133.9, 131.2, 130.8,
127.7, 127.2, 125.7, 125.0, 123.9, 120.5, 114.0, 21.9. HRMS
(EI) m/z calcd for C15H12NO4S325Cl: 368.9896 [MC], found
368.9897. Anal. Calcd for C15H12NO4S2Cl: C, 48.71; H,
3.27; N, 3.79. Found: C, 48.57; H, 3.21; N, 3.91.
3.1.13. 6-Bromo-1-phenylsulfonyl-1H-indole-3-sulfonyl
chloride (10c). To a solution of 6-bromo-1-phenylsulfonyl-
1H-indole (9c) (1.04 g, 3.1 mmol) in dry CH3CN (8 mL)
was carefully added chlorosulfonic acid (0.83 mL,
12.5 mmol) at rt. An exothermic reaction ensued, and the
resulting solution was stirred at rt for 75.5 h. The mixture
was thereafter poured on ice/water (w100 g), and extracted
with CHCl3 (50 mL, and 2!50 mL). The combined organic
extracts were washed with saturated aqueous NaHCO3
(3!50 mL), brine (50 mL), and dried over MgSO4.
Removal of the solvents in vacuo gave pure 10c
(1.18 g, 88%) as a crystalline solid with a pinkish tinge.
An analytically pure sample was obtained as pinkish
crystals by crystallization from CH3CN, mp (CH3CN)
187.5–189 8C; IR (neat) 1379, 1166, 1142, 1119, 1086, 942,
3.1.10. 1-(4-Trifluoromethyl-phenylsulfonyl)-1H-pyrrole-
3-sulfonyl chloride (8d). This compound was prepared
according to the procedure above, using 1-(4-trifluoro-
methylphenyl)sulfonyl-1H-pyrrole (7d) (0.69 g, 2.5 mmol).
Reaction time: 75.5 h. Yield: 0.54 g (58%). Colourless
crystals, mp (CH3CN) 144–145 8C; IR (neat) 1389,
1374, 1322, 1182, 1163, 1153, 1133, 1110, 1051, 1011,
1
713 cmK1; H NMR (CDCl3) d 8.10 (d, JZ8.3 Hz, 2H),
7.89 (dd, JZ2.4, 1.7 Hz, 1H), 7.89 (d, JZ8.3 Hz, 2H),
7.27 (dd, JZ3.5, 2.4 Hz, 1H), 6.77 (dd, JZ3.5, 1.7 Hz, 1H);
1
740, 721 cmK1; H NMR (CDCl3) d 8.33 (s, 1H), 8.22

T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
1705
(d, JZ1.3 Hz, 1H), 8.02–7.99 (m, 2H), 7.83 (d, JZ8.6 Hz,
1H), 7.75–7.70 (m, 1H), 7.64–7.58 (m, 3H); 13C NMR
(CDCl3) d 136.8, 135.8, 135.2, 131.4, 130.4, 129.4, 127.7,
125.3, 122.8, 121.8, 121.3, 117.1. HRMS (EI) m/z calcd for
C14H9NO4S729Br35Cl: 432.8845 [MC], found 432.8832.
Anal. Calcd for C14H9NO4S2BrCl: C, 38.68; H, 2.09; N,
3.22. Found: C, 38.66; H, 1.95; N, 3.26.
(0.74 g, 74%) as a white crystalline solid, mp (i-PrOH)
206.5–208 8C; IR (neat) 1383, 1166, 1152, 1136, 1090,
1053, 942, 735, 715 cmK1; 1H NMR (CDCl3) d 8.39 (s, 1H),
8.11 (s, 1H), 7.98 (d, JZ7.9 Hz, 1H), 7.88–7.80 (m, 3H),
7.49–7.33 (m, 5H), 7.08 (s, 1H), 2.41 (s, 3H); 13C NMR
(CDCl3) d 147.1, 136.6, 134.8, 133.9, 132.1, 131.5, 130.8,
127.6, 127.0, 125.7, 124.3, 120.0, 118.7, 117.5, 114.2, 21.9.
MS (ESIC) m/z 402 [MCH]C. Anal. Calcd for
C18H15N3O4S2: C, 53.85; H, 3.77; N, 10.47. Found: C,
53.76; H, 3.77; N, 10.36.
3.1.14. 6-Chloro-1-phenylsulfonyl-1H-indole-3-sulfonyl
chloride (10d). This compound was prepared according to
theprocedureabove,startingfrom6-chloro-1-phenylsulfonyl-
1H-indole (9d) (904 mg, 3.1 mmol). Reaction time: 68 h.
Yield: 1.08 g (89%). Colourless crystals, mp (CH3CN)
180–181 8C; IR (neat) 1390, 1379, 1186, 1166, 1144, 1122,
3.1.18. 3-(Morpholine-4-sulfonyl)-1-phenylsulfonyl-1H-
indole (12). To a solution of 10a (1.78 g, 5.0 mmol) in
CH2Cl2 (50 mL) was added morpholine (0.92 mL,
10.5 mmol) at rt. The resulting mixture was stirred at rt
for 24 h, and was thereafter washed with a mixture of water
(25 mL) and brine (25 mL). The aqueous layer was
extracted with CH2Cl2 (25 mL), and the combined organic
layers were washed sequentially with 1 M aqueous HCl
(25 mL), water (25 mL), brine (25 mL), followed by drying
over MgSO4. Removal of the solvent in vacuo gave pure 12
(1.89 g, 93%) as colourless foam. Crystallization from
ethanol gave an analytically pure sample as colourless
crystals, mp (EtOH) 150–151 8C; IR (neat) 1355, 1158,
1138, 1071, 935, 765, 727 cmK1; 1H NMR (CDCl3) d 8.13
(s, 1H), 8.04–8.00 (m, 1H), 7.98–7.94 (m, 2H), 7.90–7.86
(m, 1H), 7.66–7.61 (m, 1H), 7.55–7.50 (m, 2H), 7.47–7.42
(m, 1H), 7.39–7.33 (m, 1H), 3.76–3.73 (m, 4H), 3.12–3.09
(m, 4H); 13C NMR (CDCl3) d 137.3, 135.1, 135.0, 130.7,
130.0, 127.3, 126.5, 126.2, 125.1, 121.3, 117.5, 113.9, 66.2,
46.0. HRMS (FABC) m/z calcd for C18H19N2O5S2:
407.0735 [MCH]C, found 407.0734.
1
1087, 953, 945, 814, 749, 722 cmK1; H NMR (CDCl3) d
8.35 (s, 1H), 8.05–8.00 (m, 3H), 7.88 (d, JZ8.6 Hz, 1H),
7.75–7.70 (m, 1H), 7.64–7.58 (m, 2H), 7.45 (dd, JZ8.6,
1.7 Hz, 1H); 13C NMR (CDCl3) d 136.7, 135.8, 134.9,
133.7, 131.5, 130.4, 127.7, 126.7, 125.3, 122.4, 121.5,
114.2. HRMS (EI) m/z calcd for C14H9NO4S325Cl2:
388.9350 [MC], found 388.9338. Anal. Calcd for C14H9-
NO4S2Cl2: C, 43.09; H, 2.32; N, 3.59. Found: C, 43.17; H,
2.27; N, 3.62.
3.1.15. 5-Fluoro-1-phenylsulfonyl-1H-indole-3-sulfonyl
chloride (10e). This compound was prepared according to
the procedure above, starting from 5-fluoro-1-phenylsulfonyl-
1H-indole (9e)23 (0.853 g, 3.1 mmol). Reaction time: 72 h.
Yield: 1.16 g (100%). Colourless crystals, mp (CH3CN)
171–172 8C; IR (neat) 1386, 1174, 1167, 1159, 1108, 1086,
972, 862, 857, 849, 816, 723 cmK1 1H NMR (CDCl3)
;
d 8.40 (s, 1H), 8.01–7.97 (m, 3H), 7.73–7.68 (m, 1H),
7.64–7.56 (m, 3H), 7.28–7.21 (m, 1H). HRMS (EI) m/z
calcd for C14H9NO4S325ClF: 372.9646 [MC], found
372.9626. Anal. Calcd for C14H9NO4S2ClF: C, 44.98; H,
2.43; N, 3.75. Found: C, 44.90; H, 2.38; N, 3.71.
3.1.19. 3-(Morpholine-4-sulfonyl)-1H-indole (13).
A mixture of 12 (0.81 g, 2.0 mmol) and K2CO3 (1.11 g,
8.0 mmol) in methanol (16 mL) and water (4 mL) was
stirred at rt for 19 h. The pH was adjusted to w5 by addition
of acetic acid, and the mixture was thereafter concentrated
at reduced pressure. The residue was partitioned between
EtOAc (50 mL) and water (50 mL). The organic layer was
washed with saturated aqueous NaHCO3 (2!25 mL), brine
(25 mL), and dried over MgSO4. Evaporation of the
solvents in vacuo gave pure 13 (490 mg, 92%) as a
colourless foam. Crystallization from benzene gave an
analytically pure sample as colourless crystals, mp
(benzene) 177.5–178.5 8C; IR (neat) 3302, 1314, 1257,
1140, 1129, 1110, 1066, 936, 924, 753, 711 cmK1; 1H NMR
(CDCl3) d 9.04 (br s, 1H), 7.97–7.94 (m, 1H), 7.71 (d,
JZ3.0 Hz, 1H), 7.49–7.46 (m, 1H), 7.35–7.25 (m, 2H),
3.77–3.74 (m, 4H), 3.10–3.07 (m, 4H); 13C NMR (CDCl3) d
136.2, 130.0, 124.5, 124.3, 122.7, 120.4, 112.3, 110.7, 66.3,
46.1. HRMS (FABC) m/z calcd for C12H15N2O3S:
267.0803 [MCH]C, found 267.0797.
3.1.16. 3-(Imidazole-1-sulfonyl)-1-phenylsulfonyl-1H-
indole (11a). To a solution of 10a (1.78 g, 5.0 mmol) in
CH2Cl2 (50 mL) was added imidazole (0.73 g, 10.7 mmol).
The resulting mixture was stirred at rt for 21 h, and was
thereafter diluted with CH2Cl2 (50 mL), washed with water
(3!50 mL), followed by brine (25 mL), and dried over
MgSO4. Removal of the solvent in vacuo gave a colourless
residue, which was triturated with warm i-PrOH. The
precipitate was collected by filtration (while warm), washed
with i-PrOH, and dried to provide 11a (1.76 g, 91%) as a
white crystalline solid, mp (i-PrOH) 187–188 8C; IR (neat)
1
1376, 1149, 1140, 1089, 1035, 942, 727 cmK1; H NMR
(CDCl3) d 8.39 (s, 1H), 8.11 (s, 1H), 7.99–7.96 (m, 3H),
7.82–7.80 (m, 1H), 7.67–7.57 (m, 1H), 7.58–7.53 (m, 2H),
7.48–7.35 (m, 3H), 7.07 (s, 1H); 13C NMR (CDCl3) d 137.0,
136.6, 135.5, 134.9, 132.1, 131.5, 130.2, 127.6, 127.2,
125.8, 124.3, 120.0, 119.0, 117.5, 114.2. MS (ESIC) m/z
388 [MCH]C. Anal. Calcd for C17H13N3O4S2: C, 52.70; H,
3.38; N, 10.85. Found: C, 52.68; H, 3.50; N, 10.86.
3.1.20. tert-Butyl 1H-indole-3-carboxylate (14b).26
Oxalyl chloride (4.87 mL, 55.8 mmol) was added to a
suspension of indole-3-carboxylic acid (3.0 g, 18.6 mmol)
in anhydrous CH2Cl2 (150 mL), followed by a catalytic
amount of anhydrous DMF (four drops). The suspension
was stirred at rt for 3 h. Removal of the solvent in vacuo
gave the crude acid chloride a yellow solid. To this material
was added slightly warmed anhydrous t-BuOH (25 mL),
followed by potassium tert-butoxide (3.40 g, 30.3 mmol).
3.1.17. 3-(Imidazole-1-sulfonyl)-1-(4-methyl-phenyl-
sulfonyl)-1H-indole (11b). This material was prepared
according to the same procedure as for 11a, using 10b
(0.93 g, 2.5 mmol), and imidazole (0.37 g, 5.4 mmol) in
CH2Cl2 (25 mL). Workup as above, followed by trituration
of the crude product with warm i-PrOH gave pure 11b

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T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
The resulting viscous mixture was stirred for 90 min,
and was thereafter partitioned between Et2O (200 mL),
saturated aqueous NH4Cl (100 mL), and brine (50 mL). The
layers were separated, and the aqueous phase was extracted
with additional Et2O (100 mL). The combined organic
extracts were washed with 2 M NaOH (100 mL), water
(100 mL), and brine (100 mL), followed by drying over
Na2SO4. Removal of the solvents in vacuo gave an oily
residue, which was subjected to column chromatography
[EtOAc–CH2Cl2 (4/1)] to provide 14b (3.10 g, 77%) as a
light tan viscous oil, IR (neat) 3287, 2971, 1663, 1530,
146.8, 134.7, 134.6, 133.8, 131.9, 131.8, 130.6, 128.1,
127.4, 126.8, 125.5, 125.4, 124.5, 124.5, 122.6, 120.3,
118.6, 115.6, 114.0, 113.2, 81.6, 28.6, 21.9. Anal. Calcd for
C28H26N2O6S2: C, 61.07; H, 4.76; N, 5.09. Found: C, 61.16;
H, 4.58; N, 4.81.
3.1.23. 3-(1H-Indole-1-sulfonyl)-1H-indole (16a). To a
suspension of 15a (0.48 g, 1.1 mmol) in MeOH (12 mL) and
water (3 mL), was added K2CO3 (0.60 g, 4.3 mmol), and the
resulting mixture was stirred at rt for 22 h. Acidification to
pH w5 with AcOH, followed by concentration at reduced
pressure gave a residue, which was diluted with water
(25 mL), and extracted with EtOAc (3!25 mL). The
combined organic extracts were washed with saturated
aqueous NaHCO3 (2!25 mL), brine (25 mL), and dried
over MgSO4. Removal of the solvent in vacuo gave a solid
residue, which was subjected to column chromatography
[EtOAc–n-heptane (3/7)] to provide 16a (0.26 g, 80%) as a
white crystalline solid, mp (i-PrOH) 193.5–195 8C; IR
1
1365, 1148, 1120, 1044, 1026, 776, 741 cmK1; H NMR
(DMSO-d6) d 11.83 (s, 1H), 7.99–7.97 (m, 2H), 7.48–7.44
(m, 1H), 7.21–7.13 (m, 2H), 1.56 (s, 9H); 13C NMR
(DMSO-d6) d 164.0, 136.4, 125.5, 122.1, 121.0, 120.5,
112.2, 108.2, 78.8, 28.2.
3.1.21. 3-(1H-Indole-1-sulfonyl)-1-phenylsulfonyl-1H-
indole (15a). BuLi (2.5 M in hexanes, 3.8 mL,
10.6 mmol) was added at K78 8C to a solution of
diisopropylamine (1.33 mL, 9.5 mmol) in THF (50 mL).
After stirring at K78 8C for 20 min, indole (0.91 g, mmol)
in THF (11 mL) was added at K78 8C during w15 min. The
mixture was stirred at K78 8C for 35 min, followed by
addition of a solution of 10a (2.89 g, 8.1 mmol) in THF
(20 mL) during w10 min at K78 8C. The resulting solution
was allowed to slowly reach rt during 15 h. Saturated
aqueous NH4Cl (10 mL) was added, followed by water
(50 mL). The resulting mixture was extracted with EtOAc
(2!50 mL), and the combined organic layers were washed
with water (2!50 mL), brine (50 mL), and dried over
MgSO4. Removal of the solvents in vacuo gave a residue,
which was triturated with methanol (w30 mL). The
precipitate was collected by filtration, washed with
methanol, and dried to provide pure 15a (1.83 g, 54%) as
a slightly pinkish solid. An analytically pure sample was
obtained by crystallization from toluene as colourless
crystals, mp (toluene) 182–183.5 8C; IR (neat) 1444, 1385,
1
(neat) 3371, 1352, 1146, 1130, 1120, 1100, 742 cmK1; H
NMR (DMSO-d6) d 12.39 (br s, 1H), 8.49 (s, 1H), 7.97–7.93
(m, 2H), 7.81–7.78 (m, 1H), 7.56–7.54 (m, 1H), 7.48–7.44
(m, 1H), 7.32–7.16 (m, 4H), 6.72 (dd, JZ3.7, 0.7 Hz, 1H);
13C NMR (DMSO-d6) d 136.2, 133.7, 132.7, 130.2, 127.0,
124.0, 123.5, 122.7, 122.5, 122.1, 121.3, 118.5, 113.0,
112.9, 110.5, 107.5. HRMS (FABC) m/z calcd for
C16H12N2O2S: 296.0619 [MC], found 296.0625.
3.1.24. tert-Butyl 1-(1H-indole-3-sulfonyl)-1H-indole-3-
carboxylate (16b). To a suspension of 15b (0.60 g,
1.09 mmol) in a mixture of THF (12 mL), MeOH
(12 mL), and water (3 mL), was added K2CO3 (1.80 g,
13.0 mmol), and the resulting mixture was stirred at rt for
30 min. It was thereafter acidified to pH w5 with AcOH,
and concentrated at reduced pressure. Workup as above for
15a gave a residue, which was subjected to column
chromatography [EtOAc–n-heptane (3/7)] to afford 16b
(0.40 g, 93%) as a white crystalline solid, mp (i-Pr2O)
226 8C (dec); IR (neat) 3348, 1699, 1360, 1149, 1125, 1101,
1374, 1174, 1155, 1134, 1111, 1088, 942, 745, 726 cmK1
;
1H NMR (DMSO-d6) d 9.02 (s, 1H), 8.12–8.09 (m, 2H),
8.04 (d, JZ8.3 Hz, 1H), 7.99 (d, JZ3.7 Hz, 1H), 7.94 (d,
JZ8.2 Hz, 1H), 7.80 (d, JZ7.4 Hz, 1H), 7.72–7.67 (m, 1H),
7.58–7.51 (m, 3H), 7.46–7.33 (m, 3H), 7.26–7.21 (m, 1H),
6.75 (d, JZ3.7 Hz, 1H); 13C NMR (DMSO-d6) d 135.6,
135.5, 133.7, 133.5, 132.6, 130.3, 130.1, 127.3, 127.0,
126.8, 125.2, 124.7, 123.5, 123.4, 121.5, 119.8, 117.8,
113.6, 113.1, 109.0. HRMS (FABC) m/z calcd for
C22H16N2O4S2: 436.0551 [MC], found 436.0543.
1
1097, 965, 743 cmK1; H NMR (DMSO-d6) d 12.61 (br s,
1H), 8.68 (s, 1H), 8.39 (s, 1H), 8.04–7.96 (m, 2H), 7.83–
7.78 (m, 1H), 7.52–7.49 (m, 1H), 7.39–7.23 (m, 4H), 1.55
(s, 9H); 13C NMR (DMSO-d6) d 162.3, 136.2, 134.1, 133.8,
131.7, 126.9, 125.0, 124.0, 123.8, 122.6, 122.5, 121.5,
118.1, 113.3, 113.2, 113.0, 109.2, 80.8, 27.9. HRMS
(FABC) m/z calcd for C21H20N2O4S: 396.1144 [MC],
found 396.1126.
3.1.22. tert-Butyl 1-[1-(4-methyl-sulfonyl)-1H-indole-3-
sulfonyl]-1H-indole-3-carboxylate (15b). The procedure
above was used, employing tert-butyl indole-3-carboxylate
(14b) (1.68 g, 7.7 mmol), and 10b (3.0 g, 8.1 mmol)
dissolved in THF (25 mL). After workup, removal of the
solvents in vacuo gave a residue, which was triturated with
EtOAc (w25 mL). The precipitate was collected by
filtration, washed with EtOAc, and dried to provide 15b
(1.95 g, 46%) as a white crystalline solid, mp (EtOAc)
210–212 8C; IR (neat) 1700, 1378, 1169, 1141, 1129, 1110,
1066, 741 cmK1; 1H NMR (CDCl3) d 8.44 (s, 1H), 8.29 (s,
1H), 8.11–8.08 (m, 1H), 7.95–7.87 (m, 2H), 7.83–7.80 (m,
1H), 7.75–7.71 (m, 2H), 7.42–7.31 (m, 4H), 7.24–7.21 (m,
2H), 2.36 (s, 3H), 1.63 (s, 9H); 13C NMR (CDCl3) d 163.1,
3.1.25. 4-(1-Phenylsulfonyl-1H-pyrrole-3-sulfonyl)-
morpholine (17). The same procedure as for 12 was used,
employing 1-phenylsulfonyl-1H-pyrrole-3-sulfonyl chlor-
ide (8a) (1.53 g, 5.0 mmol), to give pure 17 (1.66 g, 93%) as
a white foamy solid. This material softens gradually at
temperatures over w80 8C, and a definite mp could not be
determined. IR (neat) 1374, 1344, 1173, 1148, 1115, 1071,
1
1054, 946, 932, 723 cmK1; H NMR (CDCl3) d 7.95–7.91
(m, 2H), 7.74–7.68 (m, 1H), 7.63 (dd, JZ2.4, 1.7 Hz, 1H),
7.62–7.56 (m, 2H), 7.25 (dd, JZ3.3, 2.4 Hz, 1H), 6.48 (dd,
JZ3.3, 1.7 Hz, 1H), 3.76–3.73 (m, 4H), 3.01–2.98 (m, 4H);
13C NMR (CDCl3) d 137.7, 135.2, 130.1, 127.5, 123.8,
123.4, 122.3, 112.2, 66.1, 46.0. HRMS (FABC) m/z calcd
for C14H18N2O5S2: 357.0579 [MCH]C, found 357.0578.

T. Janosik et al. / Tetrahedron 62 (2006) 1699–1707
1707
12. (a)Curtin,M.L.;Davidsen,S.K.;Heyman, H.R.;Garland, R. B.;
Sheppard, G. S.; Florjancic, A. S.; Xu, L.; Carrera, G. M., Jr.;
Steinman, D. H.; Trautmann, J. A.; Albert, D. H.; Magoc, T. J.;
Tapang, P.;Rhein,D.A.;Conway, R. G.;Luo, G.;Denissen, J.F.;
Marsh, K. C.; Morgan, D. W.; Summers, J. B. J. Med. Chem.
1998, 41, 74–95. (b) Sheppard, G. S.; Davidsen, S. K.;
Summers, J. B.; Carrera, G. M., Jr. U.S. Patent 5,654,305,
1997; Chem. Abstr. 1997, 127, 205591. (c) Sheppard, G. S.;
Davidsen, S. K.; Summers, J. B.; Carrera, G. M., Jr. U.S.
Patent 5,567,711, 1996; Chem. Abstr. 1996, 125, 328713.
13. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 615–617.
14. (a) Papadopoulos, E. P.; Haidar, N. F. Tetrahedron Lett. 1968,
1721–1723. (b) Wasley, J. W.; Chan, K. Synth. Commun.
1973, 3, 303–304.
3.1.26. 4-(1H-Pyrrole-3-sulfonyl)-morpholine (18). The
same procedure was used as for 13 was used, employing
compound 17 (0.71 g, 2 mmol), to afford pure 18 (0.36 g,
83%) as colourless crystals, mp (i-PrOH/i-Pr2O)
102.5–104 8C; IR (neat) 3321, 1313, 1258, 1134, 1105,
1
1066, 939, 924, 750, 724 cmK1; H NMR (CDCl3) d 9.31
(br s, 1H), 7.25–7.23 (m, 1H), 6.86–6.84 (m, 1H), 6.44–6.41
(m, 1H), 3.77–3.74 (m, 4H), 2.99–2.96 (m, 4H); 13C NMR
(CDCl3) d 122.6, 120.3, 116.7, 108.5, 66.1, 46.1. Anal.
Calcd for C8H12N2O3S: C, 44.43; H, 5.59; N, 12.95. Found:
C, 44.55; H, 5.65; N, 12.95.
3.1.27. Crystal data for 1-phenylsulfonyl-1H-pyrrole-3-
sulfonyl chloride (8a). C10H8NO4Cl, MrZ305.76, space
group: monoclinic, P21/c (No. 14). Unit-cell parameters:
˚
aZ13.597(1), bZ8.322(1), cZ11.496(1) A, aZ90, bZ
15. For a discussion, see Ref. 2, pp 39–41.
3
˚
105.34(1), gZ908, VZ1254.5(2) A , ZZ4. DxZ
16. (a) Illi, V. O. Synthesis 1979, 136. For an extension of this
excellent procedure to the synthesis of 1-phenylsulfonyl-1H-
pyrroles, see also: (b) Xu, R. X.; Anderson, H. J.; Gogan, N. J.;
Loader, C. E.; McDonald, R. Tetrahedron Lett. 1981, 22,
4899–4900.
1.619(1) g/cm3, F(000)Z624. m(Mo Ka)Z6.41 cmK1
.
Crystal dimensions 0.06!0.29!0.29 mm. A total of 1054
independent reflections [F2O3s(F2)] was refined on F2 to
give RZ0.0479, RwZ0.0934 for 165 parameters wZ1/
[s2F2oC(0.1000)Fo2]. (D/s)maxZ0.0002, (D/s)meanZ0.0000,
17. Zelikin, A.; Shastri, V. R.; Langer, R. J. Org. Chem. 1999, 64,
3379–3380.
DrmaxZ1.16 e AK3, DrminZK1.73 e A K3, Drmean
Z
˚
˚
0.32 e AK3. The data was corrected for extinction effects.
˚
18. The crystallographic data (excluding structure factors) for
compound 8a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 281814. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: C44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
References and notes
1. Nelson, K. L. In Friedel-Crafts and Related Reactions, Olah,
G. A., Ed.; Wiley: New York, 1964; Vol. 3, pp 1355–1392.
2. Cerfontain, H. Mechanistic Aspects in Aromatic Sulfonation
and Desulfonation; Wiley: New York, 1968.
19. See, for example: (a) Rokach, J.; Hamel, P.; Kakushima, M.;
Smith, G. M. Tetrahedron Lett. 1981, 22, 4901–4904. (b)
Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org.
Chem. 1983, 48, 3214–3219.
3. For numerous examples, see Ref. 2, pp 137–180.
4. Smith, G. F.; Taylor, D. A. Tetrahedron 1973, 29, 669–672.
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1990, 1341–1345.
20. Beddoes, R. L.; Dalton, L.; Joule, J. A.; Mills, O. S.; Street, J. D.;
Watt, C. I. F. J. Chem. Soc., Perkin Trans. 2 1986, 787–797.
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627–633.
6. Moranta, C.; Molins-Pujol, A. M.; Pujol, M. D.; Bonal, J.
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22. Although no spectral or physical data were given, this
compound has previously been obtained in 92% yield by
reaction of indole with NaH in DMF, followed by treatment
with benzenesulfonyl chloride, see: Sasaki, T.; Igarashi, Y.;
Ogawa, M.; Furumai, T. J. Antibiot. 2002, 55, 1009–1012.
23. 5-Fluoro-1-phenylsulfonyl-1H-indole was prepared according
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CH2Cl2 as the solvent, see: Davis, D. A. Ph.D. Thesis,
Dartmouth College, Hanover, NH, 1990.
7. (a) Terent’ev, A. P.; Yanovski, L. A. J. Gen. Chem. USSR
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Rajopadhye, M. J. Org. Chem. 1989, 54, 3264–3269. (b)
Sundberg, R. J.; Parton, R. L. J. Org. Chem. 1976, 41,
163–165.
25. Janosik, T.; Bergman, J. Unpublished work.
26. (a) Ludwig, J.; Lehr, M. Synth. Commun. 2004, 34,
ˇ
3691–3695. (b) Stanovnik, B.; Tisler, M.; Carlock, J. T.
Synthesis 1976, 754–755.
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3892–3896.
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