Iron-catalyzed sulfenylation of indoles with disulfides promoted by a catalytic amount of iodine

Article abstract of DOI:10.1055/s-0029-1217037

Selective sulfenylation of indoles with disulfides using iron(III) fluoride combined with iodine has been developed for the synthesis of sulfenylindoles. In the presence of iron(III) fluoride and iodine, a variety of disulfides underwent the reaction with indoles selectively to afford the corresponding sulfenylindoles in good to excellent yields. Moreover, reactions of indoles with 1,2-diphenyldiselane were also conducted under the same conditions, which smoothly afforded 3-selenylindoles in good yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217037

PAPER
4183
Iron-Catalyzed Sulfenylation of Indoles with Disulfides Promoted by a
Catalytic Amount of Iodine
I
ron-Catalyzed Sul
i
fenylat
a
ion of Indo
o
le
s
w
ith Disu
-
lfides Li Fang, Ri-Yuan Tang, Ping Zhong, Jin-Heng Li*
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(731)8872101; E-mail: jhli@hunnu.edu.cn
Received 24 June 2009; revised 3 August 2009
per(I) iodide catalyst at 132–160 °C was reported.6b Sub-
sequently, Uemura and co-workers have developed an
efficient protocol for the sulfenylation of indoles with thi-
ols in the presence of VO(acac)3, 2,6-di-tert-butyl-p-
Abstract: Selective sulfenylation of indoles with disulfides using
iron(III) fluoride combined with iodine has been developed for the
synthesis of sulfenylindoles. In the presence of iron(III) fluoride
and iodine, a variety of disulfides underwent the reaction with in-
doles selectively to afford the corresponding sulfenylindoles in cresol, potassium iodide and oxygen, but an excess
good to excellent yields. Moreover, reactions of indoles with 1,2-
amount of the thiol is required and undesired disulfide
byproducts are formed.10d Very recently, Yadav and co-
diphenyldiselane were also conducted under the same conditions,
which smoothly afforded 3-selenylindoles in good yields.
workers reported an iron(III) chloride catalyzed sulfeny-
lation reaction using indoles and thiols as the reaction
Key words: iron(III) fluoride, sulfenylation, indoles, disulfides,
partners;12c however, the reaction is limited to aryl thiols
sulfenylindoles, iodine
and benzyl thiol, which have a foul smell and a pungent
flavor. Here, we report a novel and efficient synthesis of
sulfenylindoles from the reaction of indoles with disul-
fides using inexpensive and environmentally benign iron
catalysts,13 inefficient catalysts in the earlier reports,6b,10d
combined with a catalytic amount of iodine (Scheme 1).
Sulfenylindoles are an important class of compounds due
to their potential utilization in many major therapeutic ar-
eas, such as in the treatment of heart disease,1 allergies,2
cancer,3 HIV4 and obesity.5 The majority of the methods
for the synthesis of sulfenylindoles involve the direct
sulfenylation of the indole nucleus with various electro-
philic sulfur reagents.6–11 The traditional electrophilic sul-
fur reagents include sulfenyl chlorides,6 quinone mono-
O,S-acetals7 and N-thiophthalimides;8 however, methods
using these sulfur reagents are limited by both the instabil-
ity, inaccessibility and/or incompatibility of the sub-
strates, and the undesired byproducts.6–8 For example,
sulfenyl chlorides, particularly with certain functional-
ities, are often unstable and difficult to prepare, and the
sulfenylation reactions result in an equivalent of thiol
byproduct. Similar disadvantages are presented in the use
of quinone mono-O,S-acetals and N-thiophthalimides.
Thus, alternative ways are conducted with the activated
disulfides9 or thiols10 in situ using a stoichiometric
amount of a promoter, such as sodium hydride,9 N-chloro-
succinimide,10a phenyliodine(III) bis(trifluoroacetate)10b
or Selectfluor™.10c Although these transformations allow
for access to sulfenylindoles in moderate to good yields,
the high promoter loadings, along with undesired toxic
byproducts, hardly make them attractive procedures. The
sulfenylation of indoles with disulfides, for instance, usu-
ally requires an excess amount of a stronger base (often
NaH), besides generating an equivalent of undesired thiol
byproduct. In view of economy and the environment, the
development of transition-metal-catalyzed sulfenylation
of indoles may be mandatory. In 1989, an example of
alkylthiation of indole with dimethyl disulfide using cop-
YR2
FeF3, I2
+
R2YYR2
2
MeCN, 80 °C
N
N
R1
R1
H
H
1
Y = S, Se
Scheme 1
The reaction of 1H-indole (1a) with 1,2-diphenyldisul-
fane (2a) was investigated to explore the optimal condi-
tions, and the results are summarized in Table 1. Initially,
a series of Lewis acids, including FeCl3, Cu(OTf)2, AuCl3
and AgOTf, were tested (entries 1–4). We found that 35%
of the 1H-indole (1a) was consumed with disulfide 2a and
iron(III) chloride after 36 hours to afford the target prod-
uct 3 in 20% yield (entry 1), and that the other Lewis acids
were inferior to iron(III) chloride (entries 2–4); however,
no reaction was observed in the absence of a Lewis acid
catalyst (entry 5). Accidently, 1 mol% of iodine was
found to enhance the yield of 3 to 75% (87% conversion
of 1a, entry 6). Although substrate 1a was converted com-
pletely at a loading of 100 mol% of iodine, a mixture of
products was observed (entry 7). Among the amounts of
iron(III) chloride and the reaction temperatures examined,
20 mol% of iron(III) chloride combined with 80 °C gave
the best results (entries 6 and 8–10). Incomplete consump-
tion of 1H-indole (1a) when using iron(III) chloride, even
with the aid of iodine, prompted us to evaluate other iron
catalysts (entries 11–14). We were delighted to observe
that substrate 1a could be converted completely with di-
sulfide 2a, giving product 3 in 90% yield, using iron(III)
SYNTHESIS 2009, No. 24, pp 4183–4189
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.10.2009
DOI: 10.1055/s-0029-1217037; Art ID: F12509SS
© Georg Thieme Verlag Stuttgart · New York

4184
X.-L. Fang et al.
PAPER
Table 1 Screening for Optimal Conditionsa
using 1 mol% of iodine alone (entry 22). These results
suggest that PhSI may be generated in situ, improving the
reaction.9,10
SPh
catalyst, I2
PhSSPh
+
As shown in Table 2, the scope of both the indole 1 and
disulfide 2 partners for the sulfenylation reaction was
screened under the standard reaction conditions. Initially,
a variety of disulfides were examined with 1H-indole (1a)
(entries 1–11). The results demonstrated that diaryl disul-
fides 2b–h, bearing either electron-donating or electron-
withdrawing groups, underwent 3-sulfenylation with 1H-
indole (1a), iron(III) fluoride and iodine smoothly in good
to excellent yields (entries 1–7). It is noteworthy that the
sulfenylation of substrate 1a with 1,2-di(pyridin-2-yl)di-
sulfane (2i) was also successful, in 88% yield (entry 8). To
our delight, the reaction conditions are compatible with
dialkyl disulfides (entries 9–11). 1,2-Dibenzyldisulfane
(2j), for instance, underwent the reaction with 1H-indole
(1a), iron(III) fluoride and iodine smoothly in 93% yield
(entry 9). Then, substituted indoles 1b–h were investigat-
ed (entries 12–23). It was found that several groups, in-
cluding bromo, ethyl and methyl, were tolerated well
under the standard reaction conditions (entries 12–18 and
21–23), but both nitro and ester groups gave unsatisfacto-
ry results (entries 19 and 20). Thus, the bromo-substituted
substrate 1b was treated with disulfides 2a, 2c or 2g to af-
ford the corresponding products 15–17 in 92%, 90% and
93% yield, respectively (entries 12–14), while methyl 1H-
indole-2-carboxylate (1f) gave the target product 23 in
only 20% yield (entry 20). The reaction of 1-methyl-1H-
indole (1g) with disulfide 2a, iron(III) fluoride and iodine
was also conducted smoothly in 71% yield (entry 21). Fi-
nally, 2-sulfenylation of the 3-substituted indole 1h was
evaluated under the standard reaction conditions (entries
22 and 23). It was interesting to discover that 3-methyl-
1H-indole (1h) was a suitable substrate to react with 1,2-
diphenyldisulfane (2a) and 1,2-di(pyridin-2-yl)disulfane
(2i) in good yields.
N
N
2a
H
H
1a
3
Entry Catalyst
(mol%)
Solvent
Conversion Yieldb
(%)
(%)
1c
2c
FeCl3 (20)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
35
20
Cu(OTf)2 (20)
AuCl3 (10)
AgOTf (10)
–
21
8
3c
<10
<10
0
<5
4c
trace
0
5c
6
FeCl3 (20)
FeCl3 (20)
FeCl3 (10)
FeCl3 (20)
FeCl3 (20)
Fe(acac)3 (20)
FeBr3 (20)
Fe (20)
87
75
7d
>99
76
mixture
63
8
9e
<5
55
trace
43
10f
11
12
13
14
15
16
17
18
19
20
21c
22
90
78
78
74
88
83
FeF3 (20)
FeF3 (10)
FeF3 (20)
FeF3 (20)
FeF3 (20)
FeF3 (20)
FeF3 (20)
FeF3 (20)
–
>99
90
90
80
52
35
DCE
65
43
toluene
DMSO
DMF
46
22
81
70
3-Selenylation of indoles with 1,2-diphenyldiselane was
also tested under the standard reaction conditions, and the
results are summarized in Scheme 2. In the presence of
iron(III) fluoride and iodine, two indoles 1a and 1b under-
went the 3-selenylation reaction with 1,2-diphenyldise-
lane (27) smoothly to afford the corresponding 3-
selenylindoles in good yields.
85
74
MeCN
MeCN
12
<10
61
65
a Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), catalyst (10–20
mol%) and I2 (1 mol%) in solvent (3 mL) at 80 °C for 36 h. Conver-
sion of 1a was determined by GC-MS analysis.
b Isolated yield.
A working mechanism, as outlined in Scheme 3, was pro-
posed on the basis of reported mechanisms.6–11 The reac-
tion can take place in the presence of iodine alone
(Table 1, entry 22), which suggests an electrophilic addi-
tion process. Initially, the reaction of RSSR (2) with io-
c Without I2.
d I2 (100 mol%).
e At room temperature.
f At 100 °C.
fluoride combined with iodine (entry 14); however, sub-
strate 1a could not be converted completely using
Fe(acac)3, FeBr3, Fe or 10 mol% of FeF3 (entries 11–13
and 15). A number of other solvents were also examined
(THF, DCE, toluene, DMSO, DMF; entries 16–20), and
they were less effective than acetonitrile. We found that
iron(III) fluoride was less effective in the absence of io-
dine (entry 21), while 61% yield of product 3 was isolated
SePh
I2 (1 mol%)
R
R
FeF3 (20 mol%)
+
PhSeSePh
MeCN, 80 °C
N
N
H
27 (0.2 mmol)
H
1 (0.4 mmol)
R = H (1a): 87% (28)
R = Br (1b): 90% (29)
Scheme 2 3-Selenylation of indoles 1 with 1,2-diphenyldiselane
(27)
Synthesis 2009, No. 24, 4183–4189 © Thieme Stuttgart · New York

PAPER
Iron-Catalyzed Sulfenylation of Indoles with Disulfides
4185
dine affords RSI (A) in situ (Scheme 3), which is followed catalyst for the electrophilic addition to give intermediate
by electrophilic addition to yield intermediate B. Deproto- B, and (2) as a promoter by reacting with HI and RSSR to
nation of intermediate B gives the desired product and afford the active RSI species, intermediate C and the sta-
HI.6 HI undergoes reaction with RSSR (2) to give an ac- ble HX (X = Br, Cl, F). The activity order of FeX3 (FeF3
tive RSI (A) and an inactive RSH intermediate. We de- > FeCl3 > FeBr3) may be dependent on the Lewis acid
duce that FeX3 plays two roles in the reaction: (1) as a
Table 2 Synthesis of Sulfenylindoles by Iron(III) Fluoride/Iodine Catalyzed Sulfenylation of Indoles 1 with Disulfides 2a
SR4
FeF3, I2
R4SSR4
R2
R2
+
MeCN, 80 °C
N
R1
N
R1
2
R3
R3
1
Entry
1
Indole
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
R3
H
H
H
H
H
H
H
H
H
H
H
Disulfide
2b
2c
R4
Product
4
Yieldb (%)
92
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
3-FC6H4
4-O2NC6H4
4-Cl-2-O2NC6H3
2-Py
2
5
96
3
2d
2e
6
93
4
7
89
5
2f
8
85
6
2g
2h
2i
9
96
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
95
8
88
9
2j
Bn
93
10
11
12
13
14
15
16
17
18
19
20
21
2k
2l
Cy
81
Me
76
5-Br
5-Br
5-Br
7-Et
H
2a
2c
Ph
92
4-MeOC6H4
4-O2NC6H4
Ph
90
2g
2a
2a
2b
2g
2a
2a
2a
93
72
1d
1d
1d
1e
Ph
93
H
4-MeC6H4
4-O2NC6H4
Ph
92
H
94
7-NO2
H
tracec
20d
71
1f
CO2Me
Ph
1g
H
H
Ph
22
23
1h
1h
2a
2i
25
26
87
89
SPh
N
H
N
H
N
S
N
H
N
H
a Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), FeF3 (20 mol%) and I2 (1 mol%) in MeCN (3 mL) at 80 °C for 36 h.
b Isolated yield based on the indole 1.
c >95% of 1e was recovered.
d >65% of 1f was recovered.
Synthesis 2009, No. 24, 4183–4189 © Thieme Stuttgart · New York

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X.-L. Fang et al.
PAPER
3-(p-Tolylthio)-1H-indole (4)10b
RSSR + I2
RSI
White solid; mp 123.5–124.4 °C.
A
2
SR
SR
1H NMR (300 MHz, CDCl3): d = 8.33 (br s, 1 H), 7.61 (d, J = 7.7
Hz, 1 H), 7.44–7.39 (m, 2 H), 7.24–7.22 (m, 1 H), 7.17–6.84 (m, 5
H), 2.24 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.5, 135.5, 134.7, 130.4, 129.5,
129.1, 126.3, 123.0, 120.8, 119.7, 111.5, 103.5, 20.9.
RSI +
N
A
N
N
H
H
H
I–
H+
1
B
LRMS (EI, 70 eV): m/z (%) = 239 (100) [M+].
RSSR + HI
RSI + RSH
2
A
3-[(4-Methoxyphenyl)thio]-1H-indole (5)10b
Pale-yellow solid; mp 112.2–114.1 °C.
1H NMR (300 MHz, CDCl3): d = 8.27 (br s, 1 H), 7.61 (d, J = 8.0
Hz, 1 H), 7.36–7.32 (m, 2 H), 7.22–7.10 (m, 4 H), 6.73–6.70 (m, 2
H), 3.74 (s, 3 H).
RSSR + HI + FeX3
RSI + RSFeX2 + HX
2
A
C
RSFeX2 + I2
RSI + FeX2I
C
A
D
13C NMR (75 MHz, CDCl3): d = 157.8, 136.5, 130.1, 129.6, 129.0,
128.6, 123.0, 120.8, 119.6, 114.5, 111.6, 104.4, 55.4.
Scheme 3 Working mechanism
LRMS (EI, 70 eV): m/z (%) = 255 (100) [M+].
properties (FeBr3 > FeCl3 > FeF3). Study of the detailed
mechanism is in progress.
3-[(4-Chlorophenyl)thio]-1H-indole (6)10b
White solid; mp 134.0–135.1 °C (Lit.2a 126–130 °C).
In summary, we have developed a novel protocol for the
synthesis of sulfenylindoles via iron-catalyzed sulfenyla-
tion of indoles with disulfides, with the aid of iodine. In
comparison with reported results,6–11 the present iron(III)
fluoride/iodine system has the advantages of high effi-
ciency, simple operation, inexpensiveness and regioselec-
tive certainty for the sulfenylation of indoles. Moreover,
1H NMR (300 MHz, CDCl3): d = 8.33 (br s, 1 H), 7.56 (d, J = 7.2
Hz, 1 H), 7.41–7.37 (m, 2 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.16 (t,
J = 7.7 Hz, 1 H), 7.08–6.98 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 137.8, 136.5, 130.8, 130.6, 128.8
(2 C), 127.2, 123.3, 121.1, 119.5, 111.8, 102.3.
LRMS (EI, 70 eV): m/z (%) = 261 (34) [M+ + 2], 259 (100) [M+],
using the iron(III) fluoride/iodine system, 3-selenylations 224 (62) [M+ – Cl].
of indoles with 1,2-diphenyldiselane can also be conduct-
3-[(4-Fluorophenyl)thio]-1H-indole (7)
White solid; mp 133.3–134.2 °C.
ed efficiently to afford the corresponding 3-selenylindoles
in good yields.
1H NMR (300 MHz, CDCl3): d = 8.32 (br s, 1 H), 7.59 (d, J = 7.8
Hz, 1 H), 7.42–7.37 (m, 2 H), 7.25–6.87 (m, 4 H), 6.84 (t, J = 8.5
Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 161.8 (d, J = 247.6 Hz, 1 C),
136.5, 134.1, 130.6, 128.9, 127.9 (d, J = 7.7 Hz, 2 C), 123.2, 121.0,
119.5, 115.8 (d, J = 21.9 Hz, 2 C), 111.7, 103.3.
LRMS (EI, 70 eV): m/z (%) = 243 (100) [M+].
HRMS (ESI): m/z calcd for C14H10FNS [M + Na]+: 266.0410;
NMR spectroscopy was performed on a Bruker Avance-300 spec-
trometer operating at 300 MHz (1H NMR) and 75 MHz (13C NMR).
TMS was used as internal standard and CDCl3 was used as the sol-
vent. Mass spectrometric analysis was performed on a Bruker Bio
TOF IIIQ spectrometer. GC-MS analysis was performed on a Shi-
madzu GCMS-QP2010 plus instrument. Melting points were
determined on a Yuhua digital melting-point apparatus and are un-
corrected.
found: 266.0401.
Iron-Catalyzed Sulfenylation of Indoles 1 with Disulfides 2 in
the Presence of Iodine; General Procedure
3-[(3-Fluorophenyl)thio]-1H-indole (8)
White solid; mp 131.2–133.1 °C.
A mixture of an indole 1 (0.4 mmol), a disulfide 2 (0.2 mmol), FeF3
(20 mol%) and I2 (1 mol%) in MeCN (3 mL) was stirred at 80 °C
for 36 h until complete consumption of the starting material, as
monitored by TLC. After the reaction was finished, the mixture was
poured into EtOAc (15 mL) and washed with sat. Na2S2O3 soln (5 ×
5 mL), followed by extraction of the aqueous layer with EtOAc (5 ×
3 mL). The combined organic layer was dried (anhyd Na2SO4) and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (hexane–EtOAc) to afford the sulfe-
nylindole product.
1H NMR (300 MHz, CDCl3): d = 8.38 (br s, 1 H), 7.59 (d, J = 7.9
Hz, 1 H), 7.44–7.39 (m, 2 H), 7.20–7.17 (m, 3 H), 6.90 (d, J = 7.8
Hz, 1 H), 6.74–6.71 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 163.0 (d, J = 247.5 Hz, 1 C),
142.2, 136.5, 131.0, 129.9 (d, J = 8.4 Hz, 1 C), 128.9, 123.3, 121.2
(d, J = 12.2 Hz, 1 C), 119.5, 112.6 (d, J = 23.8 Hz, 1 C), 111.7 (d,
J = 13.5 Hz, 1 C), 102.3.
LRMS (EI, 70 eV): m/z (%) = 243 (100) [M+].
HRMS (ESI): m/z calcd for C14H10FNS [M + Na]+: 266.0410;
3-(Phenylthio)-1H-indole (3)14
found: 266.0401.
White solid; mp 150.1–151.0 °C (Lit.14 149–151 °C).
3-[(4-Nitrophenyl)thio]-1H-indole (9)10b
Yellow solid; mp 176.1–178.0 °C.
1H NMR (300 MHz, CDCl3): d = 8.72 (br s, 1 H), 7.97 (d, J = 7.1
Hz, 1 H), 7.53–7.47 (m, 4 H), 7.30–7.10 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 150.0, 144.8, 136.6, 131.3, 128.4,
125.1, 123.9, 123.5, 121.4, 119.2, 112.0, 100.0.
LRMS (EI, 70 eV): m/z (%) = 270 (100) [M+], 223 (38), 148 (35).
1H NMR (300 MHz, CDCl3): d = 8.35 (br s, 1 H), 7.61 (d, J = 8.5
Hz, 1 H), 7.44–7.41 (m, 2 H), 7.25–7.22 (m, 2 H), 7.18–7.10 (m, 5
H).
13C NMR (75 MHz, CDCl3): d = 139.2, 136.5, 130.7, 129.0, 128.7,
125.9, 124.8, 123.1, 120.9, 119.7, 111.6, 102.8.
LRMS (EI, 70 eV): m/z (%) = 225 (100) [M+].
Synthesis 2009, No. 24, 4183–4189 © Thieme Stuttgart · New York

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Iron-Catalyzed Sulfenylation of Indoles with Disulfides
4187
3-[(4-Chloro-2-nitrophenyl)thio]-1H-indole (10)
Orange solid; mp 154.0–155.3 °C.
1H NMR (300 MHz, CDCl3): d = 8.74 (br s, 1 H), 8.24 (d, J = 2.3
Hz, 1 H), 7.56–7.45 (m, 3 H), 7.29 (t, J = 8.1 Hz, 1 H), 7.20–7.14
(m, 2 H), 6.87 (d, J = 8.7 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 8.44 (br s, 1 H), 7.76 (s, 1 H), 7.41
(s, 1 H), 7.32–7.21 (m, 2 H), 7.11 (d, J = 8.2 Hz, 2 H), 6.74 (d,
J = 8.2 Hz, 2 H), 3.72 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.0, 135.1, 131.2, 130.8, 128.9,
128.7, 125.9, 122.2, 114.6, 114.3, 113.1, 104.5, 55.4.
13C NMR (75 MHz, CDCl3): d = 144.8, 139.1, 136.8, 133.5, 131.8,
130.3, 129.1, 128.4, 125.5, 123.6, 121.5, 119.2, 112.1, 100.9.
LRMS (EI, 70 eV): m/z (%) = 335 (100) [M+ + 2], 333 (95) [M+],
320 (19) [M+ + 2 – CH3], 254 (35) [M+ – Br].
LRMS (EI, 70 eV): m/z (%) = 304 (23) [M+], 205 (33), 132 (100).
HRMS (ESI): m/z calcd for C15H12BrNOS [M + Na]+: 355.9715;
found: 355.9709.
HRMS (ESI): m/z calcd for C14H9ClN2O2S [M + Na]+: 326.9965;
found: 326.9984.
5-Bromo-3-[(4-nitrophenyl)thio]-1H-indole (17)
White solid; mp 175.8–178.0 °C.
3-(Pyridin-2-ylthio)-1H-indole (11)
Pale-yellow solid; mp 137.2–138.0 °C (Lit.1 136–137 °C).
1H NMR (300 MHz, CDCl3): d = 8.74 (br s, 1 H), 8.02 (dd, J = 7.0,
1.9 Hz, 2 H), 7.67 (s, 1 H), 7.55 (s, 1 H), 7.39–7.36 (m, 2 H), 7.11
(dd, J = 7.0, 1.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 149.2, 145.0, 135.2, 132.4, 130.3,
126.6, 125.1, 124.0, 121.8, 115.0, 113.5, 100.0.
1H NMR (300 MHz, CDCl3): d = 9.47 (br s, 1 H), 8.36 (dd, J = 3.4,
2.0 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 7.43–7.15 (m, 5 H), 6.93–
6.92 (m, 1 H), 6.80 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 162.8, 149.0, 136.8, 131.6, 128.8,
123.0, 120.9, 120.1, 119.4 (2 C), 119.3, 112.0, 100.4.
LRMS (EI, 70 eV): m/z (%) = 350 (22) [M+ + 2], 348 (23) [M+], 269
(100) [M+ – Br].
LRMS (EI, 70 eV): m/z (%) = 226 (100) [M+].
HRMS (ESI): m/z calcd for C14H9BrN2O2S [M + Na]+: 370.9460;
found: 370.9452.
3-(Benzylthio)-1H-indole (12)10b
Yellow solid; mp 85.2–87.0 °C.
7-Ethyl-3-(phenylthio)-1H-indole (18)10b
Brown oil.
1H NMR (300 MHz, CDCl3): d = 8.29 (br s, 1 H), 7.45–7.41 (m, 1
H), 7.40 (s, 1 H), 7.13–7.03 (m, 7 H), 2.89–2.81 (m, 2 H), 1.36 (t,
J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 139.3, 135.4, 130.4, 128.9, 128.7,
127.0, 125.9, 124.8, 121.6, 121.2, 117.4, 103.1, 22.8, 13.8.
1H NMR (300 MHz, CDCl3): d = 8.01 (br s, 1 H), 7.69 (d, J = 7.4
Hz, 1 H), 7.30–7.16 (m, 6 H), 7.05 (dd, J = 7.4, 1.9 Hz, 2 H), 6.91
(s, 1 H), 3.84 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.9, 136.1, 129.8, 129.1, 128.9,
128.1, 126.7, 122.5, 120.4, 119.2, 111.4, 105.0, 40.9.
LRMS (EI, 70 eV): m/z (%) = 239 (100) [M+].
3-(Cyclohexylthio)-1H-indole (13)
LRMS (EI, 70 eV): m/z (%) = 253 (100) [M+], 238 (53) [M+ – CH3].
Light-yellow solid; mp 91.0–93.1 °C.
2-Methyl-3-(phenylthio)-1H-indole (19)14
1H NMR (300 MHz, CDCl3): d = 8.21 (br s, 1 H), 7.79 (dd, J = 6.7,
2.1 Hz, 1 H), 7.36–7.19 (m, 4 H), 2.83–2.75 (m, 1 H), 1.96–1.92 (m,
2 H), 1.73–1.70 (m, 2 H), 1.36–1.15 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 136.1, 130.3 (2 C), 122.5, 120.3,
119.7, 111.3, 104.4, 47.4, 33.6 (2 C), 26.1 (2 C), 25.6.
LRMS (EI, 70 eV): m/z (%) = 231 (27) [M+], 149 (100).
HRMS (ESI): m/z calcd for C14H17NS [M + Na]+: 254.0974; found:
White solid; mp 110.9–111.2 °C (Lit.14 109–110 °C).
1H NMR (300 MHz, CDCl3): d = 8.07 (s, 1 H), 7.52 (d, J = 7.6 Hz,
1 H), 7.15–7.00 (m, 8 H), 2.42 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 141.3, 139.4, 135.5, 130.3, 128.8,
125.6, 124.6, 122.2, 120.7, 119.0, 110.8, 99.2, 12.1.
LRMS (EI, 70 eV): m/z (%) = 239 (100) [M+].
254.0962.
2-Methyl-3-(p-tolylthio)-1H-indole (20)14
Brown solid; mp 98.2–100.0 °C.
3-(Methylthio)-1H-indole (14)3
Yellow liquid.
1H NMR (300 MHz, CDCl3): d = 8.01 (br s, 1 H), 7.54 (d, J = 8.3
Hz, 1 H), 7.24–7.06 (m, 3 H), 6.95–6.93 (m, 4 H), 2.41 (s, 3 H), 2.21
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 141.1, 135.7, 135.5, 134.4, 130.4,
129.6, 125.9, 122.2, 120.7, 119.0, 110.8, 101.2, 20.9, 12.1.
1H NMR (300 MHz, CDCl3): d = 8.15 (br s, 1 H), 7.77 (d, J = 7.6
Hz, 1 H), 7.36–7.18 (m, 4 H), 2.37 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.2, 128.6, 127.8, 122.6, 120.3,
119.1, 111.5, 107.9, 20.2.
LRMS (EI, 70 eV): m/z (%) = 253 (100) [M+].
LRMS (EI, 70 eV): m/z (%) = 163 (67) [M+], 148 (100) [M+ – CH3].
2-Methyl-3-[(4-nitrophenyl)thio]-1H-indole (21)
Pale-yellow solid; mp 144.8–147.2 °C.
1H NMR (300 MHz, CDCl3): d = 8.48 (s, 1 H), 7.98 (dd, J = 8.2, 2.2
Hz, 2 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.24–
7.14 (m, 2 H), 7.08 (dd, J = 8.2, 2.2 Hz, 2 H), 2.50 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 149.9, 144.8, 141.7, 135.6, 129.6,
124.9, 123.9, 122.7, 121.1, 118.5, 110.0, 96.9, 12.1.
LRMS (EI, 70 eV): m/z (%) = 284 (100) [M+], 269 (50) [M+ – CH3].
HRMS (ESI): m/z calcd for C15H12N2O2S [M + Na]+: 307.0512;
5-Bromo-3-(phenylthio)-1H-indole (15)10b
White solid; mp 120.9–123.1 °C.
1H NMR (300 MHz, CDCl3): d = 8.42 (s, 1 H), 7.74 (t, J = 1.8 Hz,
1 H), 7.43 (d, J = 2.6 Hz, 1 H), 7.32–7.06 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 138.7, 135.1, 131.9, 130.9, 128.8,
126.1, 125.9, 125.1, 122.2, 114.5, 113.1, 102.7.
LRMS (EI, 70 eV): m/z (%) = 305 (88) [M+ + 2], 303 (94) [M+], 224
(100) [M+ – Br].
5-Bromo-3-[(4-methoxyphenyl)thio]-1H-indole (16)
found: 307.0506.
Pale-yellow solid; mp 100.1–101.8 °C.
Synthesis 2009, No. 24, 4183–4189 © Thieme Stuttgart · New York

4188
X.-L. Fang et al.
PAPER
Methyl 3-(Phenylthio)-1H-indole-2-carboxylate (23)4d
White solid; mp 173.1–174.9 °C.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (No. 20872112), Zhejiang Provincial Natural Science
Foundation of China (Nos. Y407116, Y407079, Y4080027 and
Y4080169) and Wenzhou University (No. 2007L004) for financial
support.
1H NMR (300 MHz, CDCl3): d = 9.26 (br s, 1 H), 7.58 (d, J = 8.0
Hz, 1 H), 7.46–7.09 (m, 8 H), 3.94 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 161.8, 137.6, 135.8, 129.8, 128.7,
128.5, 127.4, 126.2, 125.4, 121.8, 121.5, 112.1, 110.8, 52.3.
LRMS (EI, 70 eV): m/z (%) = 283 (10) [M+], 57 (100), 43 (91).
References
1-Methyl-3-(phenylthio)-1H-indole (24)8
White solid; mp 84.9–87.2 °C.
1H NMR (300 MHz, CDCl3): d = 7.62 (s, 1 H), 7.36–7.31 (m, 4 H),
7.18–7.10 (m, 5 H), 3.81 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 139.7, 137.6, 135.1, 129.8, 128.7,
125.7, 124.7, 122.6, 120.5, 119.7, 109.7, 100.5, 33.1.
LRMS (EI, 70 eV): m/z (%) = 239 (100) [M+].
(1) Funk, C. D. Nat. Rev. Drug Discovery 2005, 4, 664.
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Chem. 1989, 32, 1360. (b) Armer, R. E.; Wynne, G. M. PCT
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S.; Greenlee, W. J.; Balani, S. K.; Goldman, M. E.; Hoffman,
J. M. Jr.; Lumma, W. C. Jr.; Huff, J. R.; Rooney, C. S.;
Sanderson, P. E.; Theoharides, A. D. PCT Int. Appl. WO
9419321, 1994. (b) Silvestri, R.; Artico, M.; Bruno, B.;
Massa, S.; Novellino, E.; Greco, G.; Marongiu, M. E.; Pani,
A.; De Montis, A.; La Colla, P. Antiviral Chem. Chemother.
1998, 9, 139. (c) Ragno, R.; Coluccia, A.; La Regina, G.;
De Martino, G.; Piscitelli, F.; Lavecchia, A.; Novellino, E.;
Bergamini, A.; Ciaprini, C.; Sinistro, A.; Maga, G.; Crespan,
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(d) De Martino, G.; La Regina, G.; Coluccia, A.; Edler, M.
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E.; Mosley, R. T.; Tolman, R. L.; Ventre, J.; Zhang, B. B.;
Zhou, G. PCT Int. Appl. WO 0130343, 2001.
3-Methyl-2-(phenylthio)-1H-indole (25)8
White solid; mp 76.2–77.7 °C.
1H NMR (300 MHz, CDCl3): d = 7.97 (br s, 1 H), 7.60 (d, J = 7.8
Hz, 1 H), 7.28–7.04 (m, 8 H), 2.40 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.2, 136.9, 129.1, 128.5, 126.6,
125.8, 123.6, 121.5, 119.9, 119.7, 119.5, 111.0, 9.5.
LRMS (EI, 70 eV): m/z (%) = 239 (100) [M+].
3-Methyl-2-(pyridin-2-ylthio)-1H-indole (26)
White solid; mp 153.0–153.8 °C.
1H NMR (300 MHz, CDCl3): d = 8.53 (br s, 1 H), 8.42 (d, J = 4.1
Hz, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.40–7.35 (m, 2 H), 7.27–7.25
(m, 1 H), 7.18–7.16 (m, 1 H), 7.00 (d, J = 5.1 Hz, 1 H), 6.69 (d,
J = 8.1 Hz, 1 H), 2.39 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.6, 149.5, 137.1, 128.4, 123.6,
120.3, 120.1 (2 C), 119.9 (2 C), 119.7, 119.5, 111.0, 9.4.
LRMS (EI, 70 eV): m/z (%) = 240 (27) [M+], 130 (100).
HRMS (ESI): m/z calcd for C14H12N2S [M + Na]+: 263.0613; found:
(b) Ramakrishna, V. S. N.; Shirsath, V. S.; Kambhampati, R.
S.; Vishwakarma, S.; Kandikere, N. V.; Kota, S.; Jasti, V.
PCT Int. Appl. WO 2007020653, 2007.
263.0601.
3-(Phenylseleno)-1H-indole (28)15
Pale-brown solid; mp 135.4–137.0 °C.
1H NMR (300 MHz, CDCl3): d = 8.35 (br s, 1 H), 7.62 (d, J = 7.8
Hz, 1 H), 7.44–7.40 (m, 2 H), 7.24–7.10 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 136.3, 133.8, 131.2, 129.9, 128.9,
128.6, 125.6, 122.9, 120.8, 120.3, 111.3, 98.0.
LRMS (EI, 70 eV): m/z (%) = 273 (22) [M+], 193 (100).
(6) (a) Raban, M.; Chern, L. J. Org. Chem. 1980, 45, 1688.
(b) Ranken, P. F.; McKinnie, B. G. J. Org. Chem. 1989, 54,
2985. (c) Browder, C. C.; Mitchell, M. O.; Smith, R. L.; el-
Sulayman, G. Tetrahedron Lett. 1993, 34, 6245. (d) Hamel,
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5-Bromo-3-(phenylseleno)-1H-indole (29)
(8) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G. R. Org.
Lett. 2006, 8, 565.
White solid; mp 108.1–109.4 °C.
1H NMR (300 MHz, CDCl3): d = 8.42 (br s, 1 H), 7.77 (d, J = 0.9
Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.32–7.29 (m, 2 H), 7.20–7.12
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 135.0, 133.3, 132.4, 131.8, 129.1,
128.6, 125.9, 125.8, 122.9, 114.3, 112.8, 97.7.
LRMS (EI, 70 eV): m/z (%) = 353 (30) [M+ + 2], 351 (39) [M+], 273
(94), 271 (100).
HRMS (ESI): m/z calcd for C14H10BrNSe [M + Na]+: 373.9054;
found: 373.9041.
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Iron-Catalyzed Sulfenylation of Indoles with Disulfides
4189
(11) For the synthesis of sulfenylindoles via the cyclization
reactions of 2-(1-alkynyl)benzamides with sulfenyl
chlorides or disulfides, see: (a) Chen, Y.; Cho, C.-H.;
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phenols and 2-phenylpyridine, see refs. 6b, 10d and:
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Chem. Soc. 2006, 128, 6790. (c) Yadav, J. S.; Reddy, B. V.
S.; Reddy, Y. J.; Praneeth, K. Synthesis 2009, 1520.
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Synthesis 2009, No. 24, 4183–4189 © Thieme Stuttgart · New York