Synthesis of 3-(arylthio)indoles and related compounds by reactions of metalated aromatics or heterocycles with protected 3,3′-dithiobisindoles

Article abstract of DOI:10.1055/s-2007-983818

An efficient and practical strategy for the synthesis of new 3-(arylthio)indoles and related compounds has been developed, involving cleavage of readily available protected 3,3′-dithiobisindoles with metalated aromatics or heterocycles. Georg Thieme Verla

Full text of DOI:10.1055/s-2007-983818

2690
PAPER
Synthesis of 3-(Arylthio)indoles and Related Compounds by Reactions of
Metalated Aromatics or Heterocycles with Protected 3,3¢-Dithiobisindoles
S
ynthesis of 3-(A
r
a
ylthio)indo
m
i
pound
d
s
Shirani, Tomasz Janosik*
Unit for Organic Chemistry, Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, 141 57 Huddinge,
Sweden
Fax +46(8)6081501; E-mail: toja@biosci.ki.se
Received 2 April 2007; revised 30 May 2007
Consequently, there are several different strategies to-
Abstract: An efficient and practical strategy for the synthesis of
wards 3-(arylthio)- or 3-(alkylthio)indoles available in-
new 3-(arylthio)indoles and related compounds has been devel-
oped, involving cleavage of readily available protected 3,3¢-dithio-
volving, for example, such diverse sulfenylating reagents
as disulfides,5 thiols in the presence of oxygen,6 quinone-
bisindoles with metalated aromatics or heterocycles.
O,S-acetals,7 sulfenyl chlorides generated in situ,8 and N-
Key words: indoles, thioindoles, sulfides, lithiation, Grignard re-
agents
thioalkyl- or N-thioarylphthalimides.9 Some direct ap-
proaches to 3-sulfonylindoles rely on sulfonation using
chlorosulfonic acid10 or sulfonyl chlorides.11 Even though
some of these routes have been implemented for the prep-
There has been considerable interest in the chemistry of 3-
aration of specific targets, many problems associated with
(arylthio)indoles and closely related 3-sulfonylindoles, as
using very reactive, unstable, or not readily available re-
several compounds belonging to these classes have been
agents have yet to be overcome. Our preliminary results
have demonstrated that 3-(arylthio)indoles and related
heterocyclic derivatives are easily available in good yields
demonstrated to possess interesting biological effects.
The 3-(arylthio)indole 1 serves as an excellent example of
such a molecule, as it is not only an inhibitor of tubulin po-
by cleavage of readily available protected 3,3¢-dithiobis-
lymerization, but is also capable of inhibiting growth of
indoles with metalated aromatics or heteroaromatics.12
human breast cancer cells.1 Identification of the sulfone 2
Herein, we present the full details of this investigation, as
as a potent anti-HIV compound2 have triggered further
well as further potentially useful developments demon-
studies of similar 3-sulfonylindoles against HIV-1 vari-
strating the scope of this approach.
ants possessing resistance mutations.3 In addition, 3-thio-
Since our approach required access to substantial amounts
of protected 3,3¢-dithiobisindoles, the initial efforts were
directed towards development of viable routes to such
compounds. It is well established that 3,3¢-dithiobisin-
doles are formed upon exposure of indoles to thiourea in
the presence of iodine in a basic medium.13 However, this
approach appeared to suffer from generally poor yields,
and it was therefore necessary to optimize the conditions.
After some experimentation, we found that passing a
stream of air through the reaction mixture leads to a con-
siderable improvement in yields, probably by promoting
the oxidative process giving rise to disulfide formation.
Thus, treatment of the indoles 4a–c under these modified
conditions afforded the disulfides 5a–c in good yields. In-
terestingly, the 3,3¢-dithiobisindoles 5a,b proved to be re-
markably stable towards basic reaction conditions, as
treatment thereof with benzenesulfonyl chloride or p-tol-
uenesulfonyl chloride in the presence of potassium hy-
droxide and a phase-transfer catalyst14 provided the
protected derivatives 6a–c in 60–72% yield (Scheme 1).
However, initial attempts to protect the disulfides 5a or 5c
under standard conditions using di-tert-butyl dicarbonate
in the presence of DMAP as the catalyst in anhydrous
THF15 gave disappointing results. The formation of con-
siderable amounts of side products which presumably
originated from cleavage of the disulfide linkage could be
discerned in the crude mixture apart from the desired pro-
tected disulfides. In contrast, when the disulfides 5a or 5c
indole derivatives may also be encountered in nature, as
illustrated by the alkaloid echinosulfone A (3)4 (Figure 1).
MeO
OMe
MeO
MeO
O
Cl
S
S
O
CO2Me
CO2NH2
N
H
N
H
2
1
Br
O
S
O
N
CO2H
Br
N
H
3
Figure 1 Some biologically active 3-(arylthio)indoles (1, 2) and the
natural product echinosulfone A (3)
SYNTHESIS 2007, No. 17, pp 2690–2698
x
x.
x
x
.
2
0
0
7
Advanced online publication: 30.07.2007
DOI: 10.1055/s-2007-983818; Art ID: T06407SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3-(Arylthio)indoles and Related Compounds
2691
were exposed to di-tert-butyl dicarbonate and potassium illustrated by formation of compound 17 (Table 1, entry
carbonate in anhydrous DMF, the protection proceeded 11). A further extension of the scope of this strategy was
smoothly giving the products 6d–e in 82% and 88% yield, demonstrated by generation of functionalized organomag-
respectively (Scheme 1). This completed our syntheses of nesium reagents from ethyl 2-iodobenzoate or ethyl 4-io-
a small series of 3,3¢-dithiobisindoles incorporating both dobenzoate and i-PrMgCl,17 followed by reactions with
base sensitive and acid labile protecting groups.
the disulfides 6a or 6c, providing the 3-(arylthio)indoles
23–25, all featuring ester units (Table 1, entries 17–19).
The full series of products originating from the reactions
between different combinations of organometallic re-
agents and the disulfides 6a–e under various conditions is
summarized in Table 1.
H
R5
N
R2
R5
i
S
S
R2
R5
N
H
NMR spectra were recorded on a Bruker DPX 300 operating at
300.1 MHz for 1H and 75.5 MHz for 13C, using the residual solvent
signal as reference. IR spectra were acquired on a Thermo Nicolet
Avatar 330 FT-IR instrument. The elemental analyses were per-
formed by H. Kolbe Mikroanalytisches Laboratorium, Mülheim an
der Ruhr, Germany. Melting points were determined in open capil-
lary tubes on a Büchi B-545 melting point apparatus. Chemicals and
solvents were obtained from commercial sources and used as re-
ceived, except THF, which was distilled from sodium and ben-
zophenone, and DMF, which was stored over activated 4Å
molecular sieves. All reactions were performed under N2. Chroma-
tography was performed using silica gel (40–63 mm).
R2
N
H
4a R2 = R3 = H
5a R2 = R5 = H
5b R2 = H, R5 = OMe
5c R2 = Me, R5 = H
4b R2 = H, R5 = OMe
4c R2 = Me, R5 = H
R1
N
R2
ii
R5
S
S
R5
R2
3,3¢-Dithiobis(1H-indole) (5a)
N
R1
This material was prepared using a modified literature procedure.13a
A beaker was charged with indole (23.4 g, 0.2 mol), thiourea (45.6
g, 0.6 mol), EtOH (400 mL) and H2O (200 mL). To the resulting
stirred mixture were cautiously added I2 (50.8 g, 0.2 mol) and
NaOH pellets (30 g), followed by more H2O (1 L). After stirring at
r.t. for 18 h, a stream of air was passed through the mixture during
8–9 h. The crude product was collected by filtration, washed with
plenty of H2O, and was then allowed to dry. It was thereafter sus-
pended in i-Pr2O (150 mL), and stirred for ca 2 h. Filtration, wash-
ing with several small portions of i-Pr2O, and drying gave 5a (20.3
g, 68%) as a pale beige solid. The yield varied somewhat between
different runs, but was typically around 60%; mp 216–219 °C
(Lit.13a mp 227–229.5 °C).
6a R1 = SO2Ph, R2 = R5 = H
6b R1= Ts, R2 = R5 = H
6c R1 = SO2Ph, R2 = H, R5 = OMe
6d R1 = Boc, R2 = R5 = H
6e R1 = Boc, R2 = Me, R5 = H
Scheme 1 Reagents and conditions: (i) H2NCSNH2, I2, NaOH,
EtOH, H2O, r.t., 18 h, then air, r.t., 8–9 h; (ii) PhSO2Cl, Bu4NHSO4,
KOH, CH2Cl2, 0 °C 1 h, then r.t., 1.5 h (for 6a–c), or Boc2O, K2CO3,
DMF, r.t., 18 h (for 6d,e).
Having secured access to the necessary disulfides 6a–e,
experiments probing their applicability as reagents for
transfer of 3-thioindole units were undertaken (Table 1).
For instance, in situ protection and lithiation of indole at
the 2-position according to Katritzky,16 followed by reac-
tion of the resulting lithioindole with the disulfide 6a gave
the mono-protected 2,3¢-thiobisindole 7 in a moderate
yield (Table 1, entry 1). Likewise, lithiation of ben-
IR (neat): 3413, 1491, 1451, 1400, 1235, 1097, 742 cm–1.
1H NMR (DMSO-d6): d = 11.54 (br s, 2 H), 7.46–7.40 (m, 4 H),
7.31 (s, 2 H), 7.21–7.15 (m, 2 H), 7.08–7.03 (m, 3 H).
13C NMR (DMSO-d6): d = 136.6, 131.9, 128.4, 122.1, 120.0, 118.8,
112.2, 105.9.
MS (ESI–): m/z = 295 [M – H]–.
zo[b]thiophene, and subsequent quenching with 6a af- 3,3¢-Dithiobis(2-methyl-1H-indole) (5b)
The procedure described above was used, employing 2-methylin-
forded the 3-thioindole 9 (Table 1, entry 3). Similar
conditions were employed for metalation of thiophene
and benzo[b]furan, providing additional 3-(thiohetero-
aryl)indoles after introduction of appropriate disulfides 6.
In the case of benzenoid aromatics lacking additional re-
active functional groups, the substrates were first convert-
ed to their corresponding Grignard reagents by treatment
dole (13.1 g, 0.1 mol), and appropriate amounts of the reagents and
solvents, to afford 5b (11.7 g, 72%) as a cream-colored solid; mp
226–227.5 °C (Lit.18 mp 230 °C).
IR (neat): 3395, 1453, 1393, 1382, 1286, 1220, 733 cm–1.
1H NMR (DMSO-d6): d = 11.44 (br s, 2 H), 7.34–7.30 (m, 4 H),
7.12–7.00 (m, 4 H), 1.74 (s, 6 H).
with magnesium turnings in THF in the presence of cata- 13C NMR (DMSO-d6): d = 142.8, 135.5, 129.4, 121.4, 119.8, 117.9,
111.0, 102.4, 10.6.
MS (ESI–): m/z = 323 [M – H]–.
lytic amounts of iodine. The resulting organomagnesium
species were thereafter treated with suitable 3,3¢-dithio-
bisindoles 6, affording a series of 3-(arylthio)indoles, as
Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York

2692
H. Shirani, T. Janosik
PAPER
Table 1 Reactions of Metalated Aromatics or Heteroaromatics with Disulfides 6a–e
R5
SR3
R3Li or R3MgX
6a–e
R2
THF
N
R1
7–25
Entry
1
Substrate
Disulfide
Conditionsa
A
Product
Yield (%)b
6a
39
80
76
H
N
S
S
S
S
N
H
N
PhO2S
7
2
3
6a
6a
B
B
S
S
S
S
N
PhO2S
8
S
N
PhO2S
9
4
5
6b
6c
B
B
70
76
S
N
Ts
10
MeO
S
S
S
N
PhO2S
11
12
13
6
7
8
6d
6e
6a
B
B
C
62
82
75
S
S
S
S
N
Boc
O
O
N
Me
S
Boc
Br
N
PhO2S
14
Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-(Arylthio)indoles and Related Compounds
2693
Table 1 Reactions of Metalated Aromatics or Heteroaromatics with Disulfides 6a–e (continued)
R5
SR3
R3Li or R3MgX
6a–e
R2
THF
N
R1
7–25
Entry
9
Substrate
Disulfide
Conditionsa
C
Product
Yield (%)b
90
6a
Me
Br
Me
S
S
N
PhO2S
15
10
11
6a
6a
C
C
77
76
Br
OMe
OMe
N
PhO2S
16
Ph
Br
S
N
PhO2S
17
12
13
6a
6a
C
C
88
62
Br
S
N
PhO2S
18
S
S
S
Br
Br
N
PhO2S
19
14
15
16
6b
6d
6e
C
C
C
83
76
59
OMe
OMe
N
Ts
20
Br
Br
N
Boc
21
S
N
Boc
Me
22
Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York

2694
H. Shirani, T. Janosik
PAPER
Table 1 Reactions of Metalated Aromatics or Heteroaromatics with Disulfides 6a–e (continued)
R5
SR3
R3Li or R3MgX
6a–e
R2
THF
N
R1
7–25
Entry
17
Substrate
Disulfide
Conditionsa
D
Product
Yield (%)b
6a
39
CO2Et
S
I
CO2Et
N
PhO2S
23
18
19
6a
6c
D
D
69
EtO2C
CO2Et
S
I
N
PhO2S
24
75
CO2Et
I
MeO
EtO2C
S
N
PhO2S
25
a Reagents and conditions; A: (i) n-BuLi, THF, –78 °C, (ii) CO2 (g), –78 °C, (iii) t-BuLi, –78 °C, (iv) 6a, –78 °C to r.t.; B: (i) n-BuLi, THF,
–78 °C, (ii) 6a–e, –78 °C to r.t.; C: (i) Mg, I2 (cat.), THF, reflux, (ii) 6a or 6d,e, 0 °C to r.t.; D: (i) i-PrMgCl, THF, –20 to 0 °C, (ii) 6a or 6c,
–78 °C to r.t.
b Yield of purified products.
3,3¢-Dithiobis(5-methoxy-1H-indole) (5c)
IR (neat): 1443, 1369, 1259, 1199, 1173, 1123, 1105, 1092, 939,
757, 727 cm–1.
1H NMR (CDCl3): d = 8.02–7.98 (m, 2 H), 7.91–7.88 (m, 4 H),
7.62–7.48 (m, 10 H), 7.42–7.36 (m, 2 H), 7.27–7.22 (m, 2 H).
13C NMR (CDCl3): d = 137.8, 135.3, 134.5, 130.6, 130.4, 129.8,
127.1, 125.9, 124.1, 120.6, 115.8, 113.8.
Application of the procedure above, using 5-methoxyindole (7.35 g,
50 mmol) and appropriate amounts of the reagents and solvents, fur-
nished 5c (5.65 g, 63%) as an off-white solid; mp 146–148 °C
(Lit.13b mp 146–148 °C).
IR (neat): 3400, 3290, 1483, 1456, 1437, 1283, 1200, 1163, 1025,
918, 844, 802, 793 cm–1.
1H NMR (DMSO-d6): d = 11.42 (br s, 2 H), 7.35 (s, 2 H), 7.31 (d,
J = 8.7 Hz, 2 H), 6.76 (dd, J = 8.7, 2.3 Hz, 2 H), 6.68 (d, J = 2.3 Hz,
2 H), 3.50 (s, 6 H).
13C NMR (DMSO-d6): d = 154.2, 132.4, 131.3, 129.2, 112.8, 112.5,
105.8, 100.1, 54.7.
Anal. Calcd for C28H20N2O4S4: C, 58.31; H, 3.50; N, 4.86. Found:
C, 58.46; H, 3.58; N, 4.78.
3,3¢-Dithiobis[1-(4-methylphenylsulfonyl)-1H-indole] (6b)
This compound was prepared according to the same procedure as
for 6a on a 25 mmol scale. Recrystallization from MeCN (using ac-
tive charcoal) gave 6b (10.0 g, 60%) as light yellow crystals; mp
153–155 °C.
MS (ESI–): m/z = 355 [M – H]–.
3,3¢-Dithiobis(1-phenylsulfonyl-1H-indole) (6a)
IR (neat): 1444, 1363, 1170, 1122, 1109, 1089, 1039, 940, 740, 707
cm–1.
1H NMR (CDCl3): d = 8.01–7.97 (m, 2 H), 7.79–7.75 (m, 4 H),
7.59–7.55 (m, 2 H), 7.54 (s, 2 H), 7.41–7.36 (m, 2 H), 7.31–7.22 (m,
6 H), 2.37 (s, 6 H).
13C NMR (CDCl3): d = 145.8, 135.3, 134.9, 130.6, 130.4, 130.4,
127.2, 125.7, 124.0, 120.5, 115.5, 113.9, 21.8.
A stirred suspension of finely powdered KOH (12.5 g, 0.22 mol) in
CH2Cl2 (155 mL) was cooled to 0 °C, followed by sequential addi-
tion of the disulfide 5a (14.8 g, 50 mmol), and Bu4NHSO4 (0.88 g,
2.6 mmol). To this mixture, was added a solution of PhSO2Cl (16.0
mL, 0.125 mol) in CH2Cl2 (25 mL) at 0 °C during 1 h and 15 min.
The resulting mixture was stirred at 0 °C for 1 h, and thereafter at
r.t. for 1.5 h, whereupon it was filtered, and the filter cake was
washed with several portions of CH2Cl2 (4 × 25 mL). Evaporation
of the combined filtrates and washings gave a solid residue, which
was crystallized from MeCN (with active charcoal), to give 6a (20.9
g, 72%) as pinkish crystals; mp 165–166.5 °C.
Anal. Calcd for C30H24N2O4S4: C, 59.58; H, 4.00; N, 4.63. Found:
C, 59.67; H, 4.10; N, 4.60.
Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York

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Synthesis of 3-(Arylthio)indoles and Related Compounds
2695
3,3¢-Dithiobis(5-methoxy-1-phenylsulfonyl-1H-indole) (6c)
This compound was prepared according to the same procedure as
for 6a on a 12.5 mmol scale. Recrystallization from MeCN gave 6c
(5.55 g, 70%) as off-white crystals; mp 179–180 °C.
over 17 h. AcOH (1 mL) was added and stirring was continued for
15 min, followed by the addition of sat. aq NH4Cl (30 mL). The so-
lution was extracted with EtOAc (3 × 20 mL), and the combined or-
ganic phases were washed with H2O (30 mL), brine (30 mL), and
dried (Na2SO4). Evaporation of the solvents gave a residue which
was subjected to column chromatography using n-heptane–Et2O
(8:1) to provide 7 (310 mg, 39%) as off-white crystals; mp 198–
201 °C.
IR (neat): 1471, 1445, 1434, 1371, 1211, 1164, 1141, 1088, 1024,
960, 848, 723 cm–1.
1H NMR (CDCl3): d = 7.87–7.83 (m, 6 H), 7.61–7.46 (m, 8 H),
6.98–6.94 (dd, J = 9.0, 2.5 Hz, 2 H), 6.88 (d, J = 2.5 Hz, 2 H), 3.62
(s, 6 H).
13C NMR (CDCl3): d = 157.2, 137.8, 134.5, 131.9, 131.2, 129.7,
129.7, 127.0, 115.7, 115.6, 114.9, 102.3, 55.6.
IR (neat): 3380, 1443, 1364, 1340, 1170, 1130, 1112, 1089, 1047,
944, 789, 752, 741, 728 cm–1.
1H NMR (DMSO-d6): d = 11.47 (s, 1 H), 8.16 (s, 1 H), 8.07–8.04
(m, 2 H), 7.95–7.93 (m, 1 H), 7.72–7.67 (m, 1 H), 7.61–7.56 (m, 3
H), 7.44–7.24 (m, 5 H), 7.10–7.05 (m, 1 H), 6.99–6.94 (m, 1 H),
6.60–6.59 (m, 1 H).
Anal. Calcd for C30H24N2O6S4: C, 56.58; H, 3.80; N, 4.40. Found:
C, 56.67; H, 3.94; N, 4.41.
13C NMR (DMSO-d6): d = 137.4, 136.6, 134.9, 134.2, 130.2, 129.9,
129.8, 127.7, 126.9, 126.5, 125.6, 124.0, 121.9, 119.8, 119.7, 119.4,
113.4, 112.3, 111.0, 106.7.
3,3¢-Dithiobis[1-(tert-butoxycarbonyl)-1H-indole] (6d)
Di-tert-butyl dicarbonate (6.0 g, 27.5 mmol) was dissolved in anhyd
DMF (25 mL). To this solution was added the disulfide 5c (3.70 g,
12.5 mmol), followed by K2CO3 (7.60 g, 0.11 mol). The resulting
mixture was stirred at r.t. for 18 h, and was thereafter partitioned be-
tween H2O (100 mL) and CH2Cl2 (100 mL). After separation of the
layers, the aqueous phase was extracted with more CH2Cl2 (3 × 25
mL). The combined organic extracts were washed with H2O (3 × 50
mL), dried (MgSO4), and evaporated in vacuo to provide a solid res-
idue, which was finally subjected to crystallization from MeCN to
afford 6d (5.09 g, 82%) as yellow crystals; mp 170 °C.
Anal. Calcd for C22H16N2O2S2: C, 65.32; H, 3.99; N, 6.93. Found:
C, 65.06; H, 4.18; N, 6.73.
Metalation and Sulfenylation of Heterocyclic Compounds
(Conditions B, Table 1)
A solution of n-BuLi (2.5 M in hexanes, 2.0 mmol) was added over
10 min to a solution of a suitable heterocyclic compound (2.0
mmol) in anhyd THF (10 mL) at –78 °C. The solution was stirred
for 30 min at –78 °C, followed by the addition of a solution of the
appropriate disulfide (2.0 mmol) in anhyd THF (10 mL) over 15
min at –78 °C. The mixture was allowed to warm to r.t. over 16 h
and was thereafter quenched with sat. aq NH4Cl (20 mL). The re-
sulting mixture was extracted with Et2O (2 × 30 mL). The combined
organic extracts were washed with H2O (30 mL), brine (30 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was sub-
jected to column chromatography to give the products 8–13.
IR (neat): 1745, 1732, 1449, 1354, 1339, 1312, 1247, 1218, 1142,
1058, 743 cm–1.
1H NMR (CDCl3): d = 8.20 (d, J = 8.3 Hz, 2 H), 7.58–7.56 (m, 4
H), 7.42–7.36 (m, 2 H), 7.29–7.24 (m, 2 H), 1.66 (s, 18 H).
13C NMR (CDCl3): d = 149.1, 135.9, 131.2, 130.6, 125.4, 123.4,
120.3, 115.5, 114.2, 84.6, 28.3.
Anal. Calcd for C26H28N2O4S2: C, 62.88; H, 5.68; N, 5.64. Found:
C, 62.76; H, 5.75; N, 5.61.
1-Phenylsulfonyl-3-(thiophen-2-yl)thio-1H-indole (8)
Purification by column chromatography using n-heptane–EtOAc
(6:1) followed by recrystallization from MeCN gave 8 as colorless
crystals; mp 111–113 °C.
3,3¢-Dithiobis[1-(tert-butoxycarbonyl)-2-methyl-1H-indole] (6e)
This product was prepared as above using di-tert-butyl dicarbonate
(12.0 g, 55 mmol), the disulfide 5c (8.11 g, 25 mmol), and K2CO3
(15.2 g, 0.11 mol) in anhyd DMF (50 mL). Work-up as above, fol-
lowed by crystallization from MeCN afforded 6e (11.5 g, 88%) as
yellow crystals; mp 168–170 °C.
IR (neat): 1441, 1400, 1370, 1265, 1203, 1171, 1128, 1092, 942,
728 cm–1.
1H NMR (CDCl3): d = 8.00–7.96 (m, 1 H), 7.90–7.86 (m, 2 H), 7.72
(s, 1 H), 7.66–7.62 (m, 1 H), 7.59–7.53 (m, 1 H), 7.48–7.42 (m, 2
H), 7.35–7.27 (m, 3 H), 7.20 (dd, J = 3.6, 1.3 Hz, 1 H), 6.94 (dd,
J = 5.3, 3.6 Hz, 1 H).
IR (neat): 1734, 1449, 1366, 1354, 1315, 1297, 1256, 1214, 1152,
1106, 840, 745 cm–1.
1H NMR (CDCl3): d = 8.13–8.10 (m, 2 H), 7.45–7.42 (m, 2 H),
7.32–7.26 (m, 2 H), 7.23–7.17 (m, 2 H), 2.22 (s, 6 H), 1.67 (s, 18 H).
13C NMR (CDCl3): d = 150.3, 143.9, 136.0, 130.3, 124.5, 123.3,
119.4, 115.5, 113.0, 84.6, 28.4, 14.6.
13C NMR (CDCl3): d = 138.1, 135.4, 134.3, 133.5, 132.8, 130.7,
129.6, 129.4, 128.6, 127.7, 127.1, 125.7, 124.0, 120.3, 116.1, 114.0.
Anal. Calcd for C18H13NO2S3: C, 58.20; H, 3.53; N, 3.77. Found: C,
58.37; H, 3.66; N, 3.76.
Anal. Calcd for C28H32N2O4S2: C, 64.09; H, 6.15; N, 5.34. Found:
C, 64.26; H, 6.15; N, 5.32.
1-Phenylsulfonyl-3-(benzo[b]thiophen-2-yl)thio-1H-indole (9)
Purification by column chromatography using n-heptane–EtOAc
(9:1 to 4:1) followed by recrystallization from MeCN gave 9 as
white crystals; mp 140–143 °C.
2-(1-Phenylsulfonyl-1H-indol-3-yl)thio-1H-indole (7) (Condi-
tions A, Table 1)
A solution of n-BuLi (2.5 M in hexanes, 1.0 mL, 2.5 mmol) was
added dropwise to a solution of indole (234 mg, 2.0 mmol) in anhyd
THF (10 mL) at –78 °C. The resulting solution was stirred at –78 °C
for 30 min, followed by the introduction of dry CO2 (g) during 10
min. The solvent was evaporated under reduced pressure (during
that time the temperature was allowed to rise to 20 °C). N2 was in-
troduced into the vessel and the solid residue was dissolved in an-
hyd THF (10 mL), and cooled to –78 °C, followed by the dropwise
addition (over 10 min) of t-BuLi (1.7 M in pentane; 1.4 mL, 2.4
mmol) at –78 °C. The mixture was stirred for 30 min at –78 °C, fol-
lowed by the addition of 6a (1.15 g, 2.0 mmol) dissolved in THF (10
mL) during 15 min. The temperature was allowed to rise to 20 °C
IR (neat): 1444, 1377, 1266, 1174, 1129, 1109, 1090, 1047, 942,
749, 726 cm–1.
1H NMR (CDCl3): d = 8.02–7.99 (m, 1 H), 7.93–7.90 (m, 2 H), 7.86
(s, 1 H), 7.65–7.56 (m, 4 H), 7.50–7.45 (m, 2 H), 7.39–7.23 (m, 5
H).
13C NMR (CDCl3): d = 141.4, 139.9, 138.0, 136.9, 135.4, 134.4,
130.8, 130.1, 129.6, 127.1, 126.4, 125.8, 124.7, 124.6, 124.2, 123.2,
122.0, 120.4, 114.0, 113.7.
Anal. Calcd for C22H15NO2S3: C, 62.68; H, 3.59; N, 3.32. Found: C,
62.61; H, 3.68; N, 3.25.
Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York

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H. Shirani, T. Janosik
PAPER
1-(4-Methylphenylsulfonyl)-3-(benzo[b]thiophen-2-yl)thio-1H-
indole (10)
Purification by column chromatography using n-hexane–Et2O (9:1)
followed by recrystallization from MeCN gave 10 as white crystals;
mp 134–137 °C.
Generation and Sulfenylation of Aromatic Grignard Reagents
(Conditions C, Table 1)
A solution of the appropriate aryl halide (2.0 mmol) in THF (5 mL)
was added dropwise to a suspension of Mg turnings (2.2 mmol) in
anhyd THF (5 mL) at r.t. The mixture was heated at reflux for 1 h
and was thereafter cooled to 0 °C, whereupon a solution of the suit-
able disulfide (2.0 mmol) in anhyd THF (10 mL) was added during
15 min at 0 °C. The mixture was allowed to warm to r.t. over 16 h
and was thereafter quenched with sat. aq NH4Cl (20 mL). Work-up
as above, followed by column chromatography, afforded the prod-
ucts 14–22.
IR (neat): 3122, 1445, 1422, 1365, 1263, 1201, 1167, 1130, 1111,
1088, 1016, 942, 822, 810, 741, 710 cm–1.
1H NMR (CDCl3): d = 8.01–7.98 (m, 1 H), 7.87 (s, 1 H), 7.82–7.79
(m, 2 H), 7.65–7.62 (m, 2 H), 7.38–7.24 (m, 6 H), 2.37 (s, 3 H).
13C NMR (CDCl3): d = 145.6, 141.4, 139.9, 137.0, 135.3, 135.0,
130.8, 130.2, 127.2, 126.3, 125.7, 124.7, 124.5, 124.1, 123.2, 122.0,
120.3, 117.2, 113.9, 113.3, 21.8.
1-Phenylsulfonyl-3-phenylthio-1H-indole (14)
Purification by column chromatography using n-heptane–Et2O
(9:1) followed by recrystallization from MeOH gave 14 as white
crystals; mp 94–97 °C.
Anal. Calcd for C23H17NO2S3: C, 63.42; H, 3.93; N, 3.22. Found: C,
63.49; H, 3.89; N, 3.20.
5-Methoxy-1-phenylsulfonyl-3-(thiophen-2-yl)thio-1H-indole
(11)
IR (neat): 1442, 1363, 1264, 1202, 1170, 1128, 1110, 1089, 1048,
1020, 943, 811, 728 cm–1.
Purification by column chromatography using n-heptane–CH2Cl2
(9:1) followed by recrystallization from MeOH gave 11 as white
crystals; mp 125–127 °C.
1H NMR (CDCl3): d = 8.07–8.04 (m, 1 H), 7.97–7.93 (m, 2 H), 7.85
(s, 1 H), 7.62–7.56 (m, 1 H), 7.51–7.45 (m, 3 H), 7.40–7.35 (m, 1
H), 7.27–7.11 (m, 6 H).
IR (neat): 1609, 1471, 1444, 1436, 1371, 1303, 1210, 1161, 1104,
1087, 1026, 961, 841, 815, 802, 768, 752, 722 cm–1.
1H NMR (CDCl3): d = 7.88–7.83 (m, 3 H), 7.67 (s, 1 H), 7.58–7.52
(m, 1 H), 7.47–7.41 (m, 2 H), 7.28 (dd, J = 5.3, 1.3 Hz, 1 H), 7.17
(dd, J = 3.6, 1.3 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 6.97–6.92 (m,
2 H), 3.80 (s, 3 H).
13C NMR (CDCl3): d = 157.1, 138.0, 134.2, 132.6, 131.8, 129.9,
129.7, 129.5, 129.4, 129.3, 127.7, 127.0, 115.9, 115.0, 114.9, 102.3,
55.8.
13C NMR (CDCl3): d = 138.1, 136.2, 135.6, 134.3, 131.2, 130.9,
129.6, 129.2, 127.5, 127.1, 126.1, 125.7, 124.1, 120.7, 114.0, 112.4.
Anal. Calcd for C20H15NO2S2: C, 65.73; H, 4.14; N, 3.83. Found: C,
65.85; H, 4.15; N, 3.78.
1-Phenylsulfonyl-3-(3-methylphenyl)thio-1H-indole (15)
Purification by column chromatography using n-heptane–Et2O
(9:1) followed by recrystallization from MeCN gave 15 as white
crystals; mp 120–121 °C.
Anal. Calcd for C19H15NO3S3: C, 56.83; H, 3.77; N, 3.49. Found: C,
57.02; H, 3.67; N, 3.43.
IR (neat): 3155, 1444, 1364, 1265, 1205, 1171, 1163, 1129, 1111,
1090, 945, 785, 766, 729 cm–1.
1H NMR (CDCl3): d = 8.06 (d, J = 8.3 Hz, 1 H), 7.96–7.92 (m, 2 H),
7.83 (s, 1 H), 7.62–7.56 (m, 1 H), 7.51–7.46 (m, 3 H), 7.40–7.34 (m,
1 H), 7.26–7.21 (m, 1 H), 7.10 (app t, J = 7.6 Hz, 1 H), 6.98–6.89
(m, 3 H), 2.24 (s, 3 H).
13C NMR (CDCl3): d = 139.0, 138.1, 135.9, 135.6, 134.3, 131.3,
130.8, 129.6, 129.0, 128.2, 127.1, 127.1, 125.7, 124.7, 124.1, 120.7,
113.9, 112.7, 21.5.
1-(tert-Butoxycarbonyl)-3-(benzo[b]thiophen-2-yl)thio-1H-in-
dole (12)
Purification by column chromatography using n-heptane–EtOAc
(19:1) gave 12 as an off-white solid; mp 80–82 °C.
IR (neat): 1724, 1445, 1373, 1248, 1155, 1070, 808, 735 cm–1.
1H NMR (CDCl3): d = 8.20 (d, J = 8.3 Hz, 1 H), 7.94 (s, 1 H), 7.71–
7.68 (m, 1 H), 7.66–7.63 (m, 2 H), 7.39–7.24 (m, 5 H), 1.71 (s, 9 H).
13C NMR (CDCl3): d = 149.2, 141.2, 140.0, 138.1, 135.8, 130.6,
130.6, 125.5, 125.4, 124.6, 124.3, 123.6, 123.1, 122.0, 120.0, 115.6,
110.8, 84.8, 28.3.
Anal. Calcd for C21H17NO2S2: C, 66.46; H, 4.52; N, 3.69. Found:
66.32; 4.58; 3.59.
1-Phenylsulfonyl-3-(4-methoxyphenyl)thio-1H-indole (16)
Purification by column chromatography using n-heptane–Et2O
(9:1) followed by recrystallization from MeOH gave 16 as white
crystals; mp 86–88 °C.
Anal. Calcd for C21H19NO2S2: C, 66.11; H, 5.02; N, 3.67. Found: C,
66.15; H, 5.04; N, 3.67.
1-(tert-Butoxycarbonyl)-2-methyl-3-(benzo[b]furan-2-yl)thio-
1H-indole (13)
IR (neat): 1491, 1442, 1375, 1244, 1167, 1127, 1111, 1090, 1018,
943, 827, 739, 727 cm–1.
Purification by column chromatography using n-heptane–CH2Cl2
(9:1 to 5:1) gave 13 as a colorless viscous oil which solidified upon
standing; mp 96–98 °C.
1H NMR (CDCl3): d = 8.01 (d, J = 8.3 Hz, 1 H), 7.92–7.89 (m, 2 H),
7.71 (s, 1 H), 7.60–7.55 (m, 1 H), 7.49–7.44 (m, 3 H), 7.39–7.32 (m,
1 H), 7.27–7.18 (m, 3 H), 6.81–6.76 (m, 2 H), 3.77 (s, 3 H).
IR (neat): 1727, 1446, 1351, 1368, 1334, 1317, 1334, 1215, 1157,
1116, 1060, 922, 854, 819, 760, 748 cm–1.
1H NMR (CDCl3): d = 8.16–8.12 (m, 1 H), 7.75–7.72 (m, 1 H),
7.42–7.13 (m, 6 H), 6.63 (d, J = 0.9 Hz, 1 H), 2.89 (s, 3 H), 1.72 (s,
9 H).
13C NMR (CDCl3): d = 159.0, 138.1, 135.6, 134.2, 131.1, 129.6,
129.2, 127.0, 125.9, 125.6, 124.0, 120.6, 115.0, 113.9, 55.5.
Anal. Calcd for C21H17NO3S2: C, 63.77; H, 4.33; N, 3.54. Found: C,
63.85; H, 4.38; N, 3.49.
13C NMR (CDCl3): d = 156.2, 150.7, 150.3, 143.1, 135.9, 130.3,
128.8, 124.5, 124.2, 123.5, 123.0, 120.3, 119.1, 115.7, 111.2, 108.8,
107.1, 84.8, 28.4, 15.3.
1-Phenylsulfonyl-3-(biphenyl-2-yl)thio-1H-indole (17)
Purification by column chromatography using n-heptane–Et2O
(9:1) followed by recrystallization from MeOH gave 17 as white
crystals; mp 128–130 °C.
Anal. Calcd for C22H21NO3S: C, 69.63; H, 5.58; N, 3.69. Found: C,
69.38; H, 5.80; N, 3.70.
IR (neat): 1443, 1366, 1263, 1172, 1126, 1110, 1090, 949, 742, 729
cm–1.
Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York

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Synthesis of 3-(Arylthio)indoles and Related Compounds
2697
13C NMR (CDCl3): d = 8.03–8.00 (m, 1 H), 7.90–7.87 (m, 2 H),
7.69 (s, 1 H), 7.59–7.32 (m, 10 H), 7.26–7.15 (m, 3 H), 7.08–7.03
(m, 1 H), 6.84 (dd, J = 7.9, 0.9 Hz, 1 H).
13C NMR (CDCl3): d = 141.0, 140.4, 138.0, 135.6, 135.0, 134.3,
131.3, 131.1, 130.5, 129.6, 129.5, 128.4, 128.1, 127.9, 127.5, 127.0,
125.9, 125.7, 124.1, 120.7, 114.0, 112.6.
1H NMR (CDCl3): d = 8.21 (d, J = 8.3 Hz, 1 H), 7.90 (s, 1 H), 7.52–
7.49 (m, 1 H), 7.38–7.35 (m, 1 H), 7.27–7.09 (m, 6 H), 1.71 (s, 9 H).
13C NMR (CDCl3): d = 149.3, 137.2, 136.1, 131.4, 131.0, 129.1,
127.2, 125.7, 125.3, 123.5, 120.2, 115.6, 109.6, 84.6, 28.4.
Anal. Calcd for C19H19NO2S: C, 70.12; H, 5.88; N, 4.30. Found: C,
70.19; H, 5.94; N, 4.37.
Anal. Calcd for C26H19NO2S2: C, 70.72; H, 4.34; N, 3.17. Found: C,
70.83; H, 4.39; N, 3.14.
1-(tert-Butoxycarbonyl)-2-methyl-3-(1-naphthyl)thio-1H-in-
dole (22)
1-Phenylsulfonyl-3-(1-naphthyl)thio-1H-indole (18)
Purification by column chromatography using n-heptane–Et2O
(9:1) followed by recrystallization from MeCN gave 18 as white
crystals; mp 134–136 °C.
Purification by column chromatography using n-heptane–CH2Cl2
(9:1 to 5:1) gave 22 as a colorless viscous oil which solidified upon
standing; mp 58–61 °C.
IR (neat): 1731, 1451, 1369, 1352, 1333, 1314, 1256, 1214, 1153,
1112, 788, 767, 745 cm–1.
1H NMR (CDCl3): d = 8.52–8.48 (m, 1 H), 8.24–8.20 (m, 1 H),
7.89–7.86 (m, 1 H), 7.66–7.48 (m, 4 H), 7.36–730 (m, 1 H), 7.23–
7.16 (m, 2 H), 6.86 (dd, J = 7.4, 1.1 Hz, 1 H), 2.82 (s, 3 H), 1.76 (s,
9 H).
13C NMR (CDCl3): d = 150.4, 143.9, 136.3, 134.7, 134.0, 131.0,
130.6, 128.7, 126.4, 126.3, 125.9, 125.5, 124.5, 124.1, 123.5, 123.1,
119.4, 115.7, 107.5, 84.8, 28.5, 15.2.
IR (neat): 1441, 1371, 1267, 1203, 1173, 1130, 1112, 1088, 949,
788, 760, 722 cm–1.
1H NMR (CDCl3): d = 8.45–8.42 (m, 1 H), 8.07 (dd, J = 8.3, 0.6
Hz, 1 H), 7.92–7.86 (m, 3 H), 7.79 (s, 1 H), 7.70 (d, J = 8.1 Hz, 1
H), 7.62–7.53 (m, 3 H), 7.49–7.44 (m, 3 H), 7.41–7.35 (m, 1 H),
7.28–7.12 (m, 3 H).
13C NMR (CDCl3): d = 138.0, 135.7, 134.3, 134.1, 132.7, 131.7,
131.1, 130.3, 129.6, 128.8, 127.2, 127.0, 126.7, 126.7, 126.5, 125.9,
125.7, 124.5, 124.1, 120.6, 114.0, 113.1.
Anal. Calcd for C24H23NO2S: C, 74.00; H, 5.95; N, 3.60. Found: C,
74.08; H, 6.03; N, 3.52.
Anal. Calcd for C24H17NO2S2: C, 69.37; H, 4.12; N, 3.37. Found: C,
69.41; H, 4.19; N, 3.40.
Generation and Sulfenylation of Functionalized Aromatic Grig-
nard Reagents (Conditions D, Table 1)
1-Phenylsulfonyl-3-(9-phenanthren-2-yl)thio-1H-indole (19)
Purification by column chromatography using n-heptane–Et2O
(9:1) followed by recrystallization from MeCN gave 19 as white
crystals; mp 159–162 °C.
A solution of i-PrMgCl (2.0 M in Et2O, 1.2 mL, 2.4 mmol,) was
added slowly (over ~10 min) to a solution of ethyl 2-iodobenzoate
or ethyl 4-iodobenzoate (2.0 mmol) in anhyd THF (10 mL) at
–20 °C. The mixture was stirred at –20 °C for 30 min, then allowed
to warm to 0 °C over 30 min, and thereafter cooled to –78 °C. A so-
lution of the appropriate disulfide (2.0 mmol) in THF (10 mL) was
added over ~15 min at –78 °C. The resulting mixture was allowed
to warm to r.t. over 16 h, and was subsequently treated with sat. aq
NH4Cl (25 mL). Work-up as above, followed by column chroma-
tography gave the products 23–25.
IR (neat): 1444, 1363, 1258, 1172, 1123, 1108, 1088, 1048, 946,
877, 812, 746, 729, 719, 701 cm–1.
1H NMR (CDCl3): d = 8.75–8.72 (m, 1 H), 8.63 (d, J = 8.3 Hz, 1 H),
8.53–8.50 (m, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.92–7.89 (m, 2 H),
7.83 (s, 1 H), 7.77–7.66 (m, 2 H), 7.63–7.35 (m, 7 H), 7.23–7.20 (m,
1 H).
13C NMR (CDCl3): d = 138.1, 135.7, 134.3, 131.8, 131.2, 131.1,
131.0, 130.4, 130.4, 129.7, 129.6, 128.2, 127.3, 127.3, 127.2, 127.1,
127.1, 126.8, 125.8, 125.3, 124.2, 123.4, 122.8, 120.6, 114.1, 112.9.
1-Phenylsulfonyl-3-(4-ethoxycarbonylphenyl)thio-1H-indole
(23)
Purification by column chromatography using n-heptane–EtOAc
Anal. Calcd for C28H19NO2S2: C, 72.23; H, 4.11; N, 3.01. Found:
C, 72.18; H, 4.19; N, 2.97.
(8:1) gave 23 as a light yellow viscous oil.
IR (neat): 2978, 1708, 1592, 1444, 1373, 1267, 1173, 1126, 1105,
1090, 1048, 1014, 944, 756, 745, 728, 700 cm–1.
1H NMR (CDCl3): d = 8.08–8.05 (m, 1 H), 7.97–7.94 (m, 2 H), 7.91
(s, 1 H), 8.83 (d J = 8.7 Hz, 2 H), 7.63–7.57 (m, 1 H), 7.53–7.47 (m,
2 H), 7.42–7.37 (m, 2 H), 7.26–7.21 (m, 1 H), 7.06 (d J = 8.7 Hz, 2
H), 4.34 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H).
1-(4-Methylphenylsulfonyl)-3-(4-methoxyphenyl)thio-1H-in-
dole (20)
Purification by column chromatography on silica using n-heptane–
CH2Cl2 (19:1) followed by recrystallization from MeCN gave 20 as
white crystals; mp 112–114 °C.
13C NMR (CDCl3): d = 166.3, 143.1, 138.0, 135.6, 134.5, 131.8,
130.9, 130.2, 129.7, 127.8, 127.1, 125.9, 125.9, 124.3, 120.5, 114.1,
110.4, 61.1, 14.5.
IR (neat): 1589, 1491, 1443, 1372, 1289, 1267, 1249, 1173, 1156,
1105, 1089, 1041, 1025, 941, 831, 812, 761, 744, 721, 712 cm–1.
1H NMR (CDCl3): d = 8.02–7.98 (m, 1 H), 7.79 (d J = 8.4 Hz, 2 H),
7.71 (s, 1 H), 7.48–7.44 (m, 1 H), 7.37–7.31 (m, 1 H), 7.27–7.19 (m,
4 H), 6.78 (d, J = 9.0 Hz, 2 H), 3.77 (s, 3 H), 2.37 (s, 3 H).
Anal. Calcd for C23H19NO4S2: C, 63.14; H, 4.38; N, 3.20. Found: C,
62.97; H, 4.37; N, 3.15.
13C NMR (CDCl3): d = 158.9, 145.5, 135.6, 135.2, 131.1, 131.0,
130.2, 129.4, 127.1, 126.0, 125.5, 123.9, 120.5, 114.9, 114.5, 113.9,
55.5, 21.8.
1-Phenylsulfonyl-3-(2-ethoxycarbonylphenyl)thio-1H-indole
(24)
Purification by column chromatography using n-heptane–EtOAc
(9:1) gave 24 as a colorless viscous oil which solidified upon stand-
ing; mp 108–110.5 °C.
Anal. Calcd for C22H19NO3S2: C, 64.52; H, 4.68; N, 3.42. Found: C,
64.60; H, 4.74; N, 3.36.
IR (neat): 1702, 1443, 1366, 1267, 1252, 1174, 1131, 1091, 1039,
944, 762, 752, 742, 728 cm–1.
1H NMR (CDCl3): d = 8.08–8.02 (m, 2 H), 7.97–7.93 (m, 2 H), 7.90
(s, 1 H), 7.62–7.56 (m, 1 H), 7.51–7.46 (m, 2 H), 7.41–7.36 (m, 2
1-(tert-Butoxycarbonyl)-3-phenylthio-1H-indole (21)
Purification by column chromatography using n-heptane–EtOAc
(19:1) gave 21 as light yellow oil.
IR (neat): 1734, 1448, 1354, 1311, 1246, 1218, 1149, 1060, 737
cm–1.
Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York

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H. Shirani, T. Janosik
PAPER
H), 7.25–7.19 (m, 1 H), 7.14–7.09 (m, 2 H), 6.69–6.66 (m, 1 H),
4.46 (q, J = 7.1 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3): d = 166.6, 141.6, 138.0, 135.8, 134.4, 132.5,
132.3, 131.4, 131.3, 129.6, 127.1, 126.8, 126.6, 125.8, 124.5, 124.2,
120.7, 114.0, 111.9, 61.5, 14.5.
Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’Brien,
J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.;
Anderson, P. S. J. Med. Chem. 1993, 36, 1291.
(3) (a) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.;
Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.;
La Colla, P. J. Med. Chem. 2003, 46, 2482. (b)Silvestri, R.;
Artico, M.; De Martino, G.; La Regina, G.; Loddo, R.; La
Colla, M.; La Colla, P. J. Med. Chem. 2004, 47, 3892.
(4) Ovenden, S. P. B.; Capon, R. J. J. Nat. Prod. 1999, 62, 1246.
(5) Atkinson, J. G.; Hamel, P.; Girard, Y. Synthesis 1988, 480.
(6) Maeda, Y.; Koyabu, M.; Nishimura, T.; Uemura, S. J. Org.
Chem. 2004, 69, 7688.
(7) Matsugi, M.; Murata, K.; Gotanda, K.; Nambu, H.;
Anilkumar, G.; Matsumoto, K.; Kita, Y. J. Org. Chem. 2001,
66, 2434.
(8) Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed,
J. E.; Sexton, K. Org. Lett. 2004, 6, 819.
Anal. Calcd for C23H19NO4S2: C, 63.14; H, 4.38; N, 3.20. Found: C,
63.25; H, 4.32; N, 3.12.
5-Methoxy-1-phenylsulfonyl-3-(2-ethoxycarbonylphenyl)thio-
1H-indole (25)
Purification by column chromatography using n-heptane–CH2Cl2
(4:1) gave 25 as white crystals; mp 114–117 °C.
IR (neat): 1704, 1460, 1446, 1434, 1372, 1267, 1250, 1212, 1164,
1140, 1100, 1090, 1029, 957, 851, 825, 810, 744, 724 cm–1.
1H NMR (CDCl3): d = 8.06–8.03 (m, 1 H), 7.97–7.90 (m, 3 H), 7.84
(s, 1 H), 7.62–7.57 (m, 1 H), 7.53–7.46 (m, 2 H), 7.15–7.09 (m, 2
H), 6.99 (dd, J = 9.0, 2.5 Hz, 1 H), 6.83 (d, J = 2.5 Hz, 1 H), 6.67–
6.64 (m, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 3.70 (s, 3 H), 1.46 (t, J = 7.1
Hz, 3 H).
13C NMR (CDCl3): d = 166.7, 157.4, 141.7, 138.0, 134.3, 133.1,
132.7, 132.6, 131.5, 130.3, 129.6, 127.1, 126.8, 126.5, 124.5, 115.4,
115.1, 111.8, 102.4, 61.5, 55.9, 14.6.
(9) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G. R. Org.
Lett. 2006, 8, 565.
(10) Janosik, T.; Shirani, H.; Wahlström, N.; Malky, I.;
Stensland, B.; Bergman, J. Tetrahedron 2006, 62, 1699.
(11) (a) Yadav, J. S.; Reddy, B. V. S.; Krishna, A. D.; Swamy, T.
Tetrahedron Lett. 2003, 44, 6055. (b) Singh, D. U.; Singh,
P. R.; Samant, S. D. Tetrahedron Lett. 2004, 45, 9079.
(12) Shirani, H.; Stensland, B.; Bergman, J.; Janosik, T. Synlett
2006, 2459.
(13) (a) Woodbridge, R. G. III; Dougherty, G. J. Am. Chem. Soc.
1950, 72, 4320. (b) Piotrowska, H.; Serafin, B.; Wejroch-
Matacz, K. Rocz. Chem. 1975, 49, 635; Chem. Abstr. 1975,
83, 79019.
Anal. Calcd for C24H21NO5S2: C, 61.65; H. 4.53; N, 3.00. Found: C,
61.76; H, 4.62; N, 2.94.
Acknowledgment
‘Magn. Bergwalls Stiftelse’ is gratefully acknowledged for finan-
cial support.
(14) (a) Illi, V. O. Synthesis 1988, 136. (b) Conway, S. C.;
Gribble, G. W. Heterocycles 1990, 30, 627.
(15) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl.
1984, 23, 296.
(16) Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 26,
References
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Synthesis 2007, No. 17, 2690–2698 © Thieme Stuttgart · New York