Microwave-assisted regioselective sulfenylation of indoles under solvent- and metal-free conditions

Article abstract of DOI:10.1039/c5ra26425a

Herein, we report a solvent- and metal-free methodology for the sulfenylation of indoles with sulfinic acids in the absence of an external catalyst under microwave irradiation. This environmentally friendly approach offered the desired products in moderate to excellent yields in only 10 min. Several functional group tolerances were monitored under the optimized conditions.

Full text of DOI:10.1039/c5ra26425a

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DOI: 10.1039/C5RA26425A
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ARTICLE
Microwave-assisted regioselective sulfenylation of indoles under
solvent- and metal-free conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Rajjakfur Rahaman, Namita Devi, Jyoti Rekha Bhagawati and Pranjit Barman*
Herein, we report a solvent- and metal-free methodology for the sulfenylation of Indoles with sulfinic acids in the absence
of external catalyst under microwave irradiation. This environmental friendly approach offered the desired products in
moderate to excellent yields in only 10 min. Several functional group tolerances were monitored under the optimized
conditions.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Cl
O
Cl
Cl
Cl
Introduction
Me
NH
S
H
S
Cl
N
S
O
Sulfenylated indole moieties are an important class of
organosulfur compounds as they are present in many
pharmaceutically and biologically important molecules.1 Among the
sulfenylated indole derivatives, 3-sulfenylindoles have attracted
considerable interest due to their greater therapeutic value in the
treatment of several diseases (Chart 1), such as, HIV,2 heart
disease,3 cancer,4 obesity5 and allergies.6 They are also used as
potent inhibitor in tubulin polymerization.7 These fascinating
biological profiles are the basic cause of long standing interest in
the development of efficient methods for the synthesis of 3-
sulfenylindoles. In the last few decades, a number of significant
methods have been developed. Variety of sulfenylating reagents
have been discovered as reaction partners during the synthetic
efforts. For example, sulfenyl halides,8 disulfides,9 thiols,10 quinine
mono-O,S-acetals,11 arylsulfonyl chlorides,12 N-thioimides,13
sulfonium salts,14 and sulfenyl hydrazides15 are the most effective
thiolating reagents for the synthesis of 3-sulfenylindoles.
Although several methodologies have been reported for the
reaction of electrophilic sulfur species to indoles, but in most of the
cases, they require long reaction times, harsh reaction conditions
(such as stoichiometric strong base), toxic reagents, and use of large
amount of metals and/or solvents. Thus, development of a new
environmentally friendly synthetic method for the sulfenylation of
indoles remains an important challenge in organic synthesis.
S
Me
OH
O
O
O
N
N
H
O
respiratory disorders
vascular
Chart 1 Some biologically active 3-arylthioindoles
In organic transformations, such as, C-S and C-Se bond
formations,16 the use of microwave irradiation can provide
excellent yield in a very short reaction time.17 In addition, with the
development of sustainable technologies, solvent-free conditions
have emerged as a benign alternative for organic synthesis.18 In the
existing green chemistry scenario, microwave assisted organic
synthesis (MAOS) has attained the status of a new and fascinating
discipline.19 Microwave irradiation and solvent-free microwave-
assisted techniques have been used for the rapid synthesis of
various compounds, which have received special attention in recent
years.20 With the assistance of microwave irradiation, reactions can
proceed faster to give higher yields, as compared to conventional
methods.
Braga and co-workers21 reported a highly efficient and solvent-
free method for the synthesis of 3-chalcogenyl-indoles. They have
used disulfides as sulfenylating agents, DMSO as a stoichiometric
oxidant, and molecular iodine (I2) as catalyst, under microwave
irradiation.
Thiols and disulfides were used as sulfenylating agents in many
cases, but they have some practical limitations. Thiols are toxic,
volatile, and foul smelling, where as disulfides are expensive and
moisture sensitive. In addition, disulfide needs to be prepared via
oxidative coupling of thiols; an extra operational step which causes
low atom economy.22
OCH3
OCH3
S
S
Cl
H3CO
OCH3
CO2CH3
CONH2
N
H
N
H
anti-HIV
anti-cancer
Recently, Liu et al. reported the sulfenylation of indoles,
employing sulfinic acids as sulfenylating agents.23 Sulfinic acids are
easily accessible, less costly, and are employed to form sulfones,
which have versatile applications in medicinal chemistry.24
Moreover, sulfinic acids can also be reduced to disulfides, which are
efficient sulfenylating agents. Taking this idea, herein, we report a
a.Department of Chemistry, National Institute of Technology Silchar, Silchar
788010, India. Fax: +91 3842 224797; Tel: +91 9435374128; Email:
barmanpranjit@yahoo.co.in.
Electronic Supplementary Information (ESI) available: [1H NMR and 13C NMR
spectra of synthesized compounds]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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fast and efficient method for the sulfenylation of indoles in the Results and discussion
View Article Online
DOI: 10.1039/C5RA26425A
absence of solvent, under microwave irradiation (Scheme 1). The
The reaction conditions were optimized for indole 1a and
benzenesulfinic acid 2a taken as model substrates in the presence
of tetrabutylammonium iodide (n-Bu4NI) and p-toluenesulfonic acid
(Table 1). The reaction was carried out for reaction times of 3, 5, 7,
and 10 mins. The reaction for 10 min offered the desired product in
highest yield (Table 1, entry 4).
combination of a solvent-free reaction medium with microwave
irradiation have been used successfully for the synthesis of 3-
sulfenylation of indoles.25 However, to date, there are no reports of
studies in which this attractive strategy has been applied to the
synthesis of 3-sulfenylindoles. The protocol we have reported has a
broad substrate scope, green reaction conditions, and high yields in
a short reaction time.
In the next step, we examined the effect of temperature and
influence of microwave irradiation in terms of yield. It was observed
o
that at 70 C and 110 W, the desired product 3a gives maximum
R2
yield of 97 % (Table 1, entry 4).
N
R1
R2
SR
Additionally, we examined the reaction under conventional
heating in oil bath and at room temperature, which gives the
desired product in 80 % and 76 % yield respectively. However,
these processes required a very long reaction time (Table 1,
entry 9 and 10).
0.5 eq.
+
n-Bu4NI (0.6 eq.), TsOH (0.2 eq.)
R2
or
SR
MW (110 W), 10 min, 70 o
C
N
R1
N
R1
RSO2H
0.6 eq.
"SOLVENT FREE"
Scheme 1 3-Sulfenylation of indoles under solvent-free conditions
Table 1 Optimization of microwave parameters and reaction conditionsa
SPh
n-Bu4NI (mmol), Acid (mmol)
MW, temperature, time
+
PhSO2H
N
N
H
H
2a
1a
3a
Entry
1
1a/2a (mmol)
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
0.5/0.6
MW (W)
110
110
110
110
110
110
110
110
110
110
110
110
110
110
150
70
T (oC)
Time (min)
Additive (mmol)
Acid (mmol)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.1)
TsOH (0.05)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
HCl (0.2)
Yield(%)b
40
70
70
70
70
70
70
80
60
70
70
70
70
70
70
70
70
70
70
70
70
r.t.
3
5
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.5)
n-Bu4NI (0.25)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
n-Bu4NI (0.6)
NaI (0.6)
2
65
3
7
75
4
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
18 h
48 h
95
5
75
6
45
7
85
8
73
9
85
10
11
12
13
14
15
16
17
18
19
20
21
75
40
70
TfOH (0.2)
H2SO4 (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
85
45
86
64
110
110
110
-
20
KI (0.6)
10
-
0
n-Bu4NI (0.6)
80c
76d
-
n-Bu4NI (0.6)
b
aReaction conditions: indole 1a (0.5 mmol), benzenesulfinic acid 2a (0.6 mmol). Isolated yield. Conventional heating. Reaction performed
c
d
without microwave irradiation at room temperature.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA26425A
After that, additive loading was screened to improve the yield of
the product. On increasing the amount of additive (n-Bu4NI) to 0.6,
0.5, and 0.25 mmol; the desired product was obtained with 85, 75,
and 40 % yield (Table 1, entries 9-11). Thus, the additive loading
was optimized at 0.6 mmol. However, there was no product
formation without using n-Bu4NI (Table 1, entry 19). Other
additives, such as NaI and KI were also evaluated, but were not as
effective as n-Bu4NI (Table 1, entries 17, 18).
S
S
S
Cl
Br
N
N
N
H
H
H
3g, 96 %
3h, 90 %
3i, 87 %
S
S
Br
S
MeO
Br
Br
N
N
H
N
H
The effect of acids, such as, TsOH, HCl, TfOH, and H2SO4 were
studied. It was observed that TsOH provided the desired product in
highest yield, when used in stoichiometric amount. The best molar
ratio of indole/sulfinic acid was found to be 0.5/0.6 (Table 1).
With the optimized reaction conditions in hand (Table 1, entry 4),
the scope and limitations of the proposed method were
investigated. First, we study the substrate scope of arylsulfinic acids
towards indole (1a). A variety of arylsulfinic acids with electron
donating and electron withdrawing groups were smoothly reacted
with indole to form their corresponding 3-arylthioindoles, with
moderate to excellent yields (Table 2). The arylsulfinic acids with
electron donating groups, such as, –Me and –OMe on the phenyl
ring produced the desired products with higher yields than those
with electron withdrawing groups (−Cl, −Br, and −NO2). Thereafter,
we have investigated the substrate scope of indoles. Similar trends
were observed for indoles, where reactions with electron donating
groups (−Me and −OMe) gives products with higher yields than
those with electron withdrawing groups (−Br and −NO2). N-
substituted indoles also offered the corresponding products with
higher yields, without any difficulties. In general, sulfenylation
occurs at 3-position of the indole ring (Table 2, 3a-3s). However, 2-
position of the indole ring becomes the active reaction site, when 3-
position is occupied by alkyl groups, such as, −Me (Table 2, 4a). No
by-product (bis-2,3-arylthioindole) is obtained under the optimized
reaction conditions.
H
3j, 89 %
3k, 92 %
3l, 97 %
S
S
S
O2N
N
H
N
H
N
H
3m, 72 %
3n, 95 %
3o, 87 %
S
S
S
N
N
H
N
H
CH3
3q, 95 %
3p, 85 %
3r, 78 %
S
(CH2)7Me
S
N
H
N
H
3s, 68 %
4a, 96 %
aReaction conditions: indole 1 (0.5 mmol), sulfinic acid 2 (0.6 mmol), n-
Bu4NI (0.6 mmol), TsOH (0.2 mmol), MW (110 W), 10 min, 70 oC.
bIsolated yield.
To demonstrate the synthetic utility of the new method, gram
scale reaction was carried out under the optimized conditions
(Scheme 2). Thereby, the reaction between 1H-indole 1a and
benzenesulfinic acid 2a, n-Bu4NI, and TsOH were taken in a 25 mL
sealed glass vial and placed in the Milestone Srl microwave reactor.
After, 45 min of reaction time the desired product 3a obtained in 80
% yield.
Table 2 Substrates scope for the Reaction of indoles 1 with sulfinic acids
2a,b
R2
SR
R2
N
R1
n-Bu4NI, TsOH
Ph
S
R2
1
+
SR
or
n-Bu4NI (6 mmol), TsOH (2 mmol)
MW (110 W), 10 min
N
R1
N
R1
+
PhSO2H
70 o
C
RSO2H
N
4
MW (110 W), 45 min, 70 o
C
N
3
H
2
H
2a
1a
5 mmol
3a
80%
6 mmol
S
S
S
Cl
Scheme 2 Scale-up reaction between 1a and 2a
N
H
N
N
H
H
3a, 95 %
3b, 94 %
3c, 92 %
O2N
In order to gain insight of the reaction mechanism, a control
experiment was carried out with benzenesulfinic acid 2a, in the
absence of indole 1a. This led to the formation of corresponding
disulfide with excellent yield under optimized conditions (Scheme
3).23 During the reaction process, a purple colouration of the
reaction mixture was observed, which confirmed the formation of
iodine. In the presence of 20 mol % of iodine, indole 1a reacted
with diphenyl disulfide 5a to give corresponding 3-sulfenylindole 3a
S
NO2
S
Br
S
N
H
N
H
N
H
3e, 88 %
3d, 93 %
3f, 85 %
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in 95 % yield. However, no product was formed on the treatment of Conclusions
diphenyl disulfide 5a with indole 1a, under the optimized reaction
conditions.
View Article Online
DOI: 10.1039/C5RA26425A
We have developed a fast, economic, and highly efficient MW-
assisted synthetic method for the regioselective 3-sulfenylation of
indoles using sulfinic acids as thiolating agent. The new approach
gives the desired products in excellent yields in only 10 min, under
metal- and solvent-free conditions. Important advantages
associated with this methodology are: no side product is obtained
on the completion of the reactions and the by-product I2 acts as an
efficient catalyst. Due to excellent yield, short reaction time, and
solvent-free conditions, this methodology promises to be a practical
and greener alternative to earlier methods. This study will open a
new window to many other useful transformations in organic
synthesis. Further studies on the application of sulfinic acids are
underway in our laboratory.
n-Bu4NI, TsOH
S
Ph
PhSO2H
I2
Ph
S
+
MW (110 W), 10 min, 70 o
C
2a
5a, 95 %
Ph
S
I2 (20 mol %)
S
Ph
+
Ph
S
N
H
N
MW (110 W), 10 min
70 o
H
5a
C
1a
3a, 80 %
n-Bu4NI, TsOH
S
Ph
+
no reaction
Ph
S
N
MW (110 W), 10 min
H
5a
70 o
C
1a
Experimental
Scheme 3 Control experiments
General methods and materials: All chemicals were purchased
from commercially available sources and were used without further
purification. Melting points were recorded on an electro thermal
On the basis of previous reports,9d,23,26 above experimental
results, and control experiments, we proposed a plausible
mechanism for 3-sulfenylation of indoles, as illustrated in Scheme 4.
The stepwise removal of hydrogen and oxygen atoms from the
SO2H group in sulfinic acid 2 in the presence of n-Bu4NI and TsOH,
led to the formation of RSI. Alternatively, sulfenyl iodide reacts with
2 to give the sulfonothioate G. Reduction of G by n-Bu4NI/TsOH
gives disulfide H.15 Disulfide H reacts with I2, which is produced in
the earlier step to form sulfenyl iodide (F).9d,21 In the next step,
indole 1 reacts with the sulfenyl iodide to form the intermediate I. I
give the desired product 3. However, product 4 is formed when a
substituent occupy the C-3 positions of indole 1. HI reacts with
sulfinic acid and regenerate I2.
1
digital melting point apparatus and were uncorrected. H and 13C
NMR spectra were recorded in CDCl3, DMSO-d6 and D2O at 600
MHz, 400 MHz, 150 MHz, 125 MHz, and 100 MHz. Chemical shifts
(δ) are reported as parts per million (ppm) and are referenced to
tetramethylsilane (TMS) as internal standard. NMR multiplicities are
abbreviated as follows: s = singlet, d = doublet, t = triplet, m =
multiplet, br = broad signal. Microwave-assisted syntheses were
carried out in a monomode Milestone Srl microwave reactor. All
reactions were performed in commercially available 10 mL sealed
glass tubes. TLC was done on silica gel coated glass slide (Merck
silica gel G for TLC). For column chromatography, silica gel 60-120
mesh (SRL, India) was used. Elemental analyses were performed on
a Flash 2000 Thermo Scientific instrument. The yields are based on
isolated compounds after purification.
OH
S
OH
OH
O
H
R
S
R
S
R
OH
OH
Typical procedure for the synthesis of 3-sulfenylindoles: Mixture of
2
A
I
I
B
indole
1
(0.5 mmol), sulfinic acid
2
(0.6 mmol),
O
S
OH2
S
OH
S
tetrabutylammonium iodide (221.5 mg, 0.6 mmol), and TsOH (35.5
mg, 0.2 mmol) were taken in a sealed glass tube (10 mL) and placed
in the microwave reactor. A maximum irradiation power of 110 W
and 70 oC were applied for 10 min. When the temperature reached
H
H
I
R
I
I
I
R
R
H2O
I
I
C
D
E
I
H2O, I2
I2
o
70 C, the instrument automatically adjust to maintain a constant
O
S
[H]
O
S
temperature. After 10 min, the reaction mixture was cooled to
room temperature. The reaction mixture was quenched with 10 mL
aqueous solution of 10 % sodium thiosulfate and the organic layer
was extracted with ethyl acetate (3 x 10 mL). The organic layer was
dried over anhydrous Na2SO4, filtered, and the solvent was
removed under vacuum. The crude was purified by column
chromatography on silica gel, with petroleum ether/ethyl acetate
(15:1) as the eluent, to get the desired product 3.
S
S
R
+
R
S
R
I
R
R
S
R
I
R
S
HI
H2O
OH
F
O
G
F
H
2
R2
N
R1
1
R2
SR
SR
H
R2
R2
SR
or
HI
N
I
N
N
R1
R1
R1
I
4
3
3-(phenylthio)-1H-indole (3a).15 107 mg, Yield: 95 %; White solid;
o
1
m.p. 151–152 C; H NMR (400 MHz, CDCl3): δ = 8.40 (br s, 1 H),
7.66 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 2.4 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1
H), 7.32 (t, J = 7.2 Hz, 1 H), 7.22–7.18 (m, 3 H), 7.15 (d, J = 7.6 Hz, 2
Scheme 4 Plausible reaction mechanism for the 3-sulfenylation of
indoles
4 | J. Name., 2012, 00, 1-3
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H), 7.11 (t, J = 7.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3): δ=139.1, s, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 1VHiew), A7rt.i2cl7e O(tn,linJ=e
DOI: 10.1039/C5RA26425A
136.3, 130.5, 128.9, 128.5, 125.7, 124.6, 122.9, 120.8, 119.5, 111.4, 7.2, 1 H), 7.22-7.17 (m, 3 H), 7.11 (d, J = 7.2 Hz, 3 H), 2.57 (s, 3 H);
102.6; Anal. Calcd. for C14H11NS: C, 74.63; H, 4.92; N, 6.22 %. Found: 13C NMR (125 MHz, CDCl3); Anal. Calcd. for C15H13NS: C, 75.28; H,
C, 74.61; H, 4.91; N, 6.23 %.
5.47; N, 5.85 %. Found: C, 75.25; H, 5.45; N, 5.83 %.
3-(p-Tolylthio)-1H-indole (3b).15 112 mg, Yield: 94 %; White solid; 5-Bromo-3-(p-chlorophenylthio)-1H-indole (3i).13b 151 mg, Yield: 89
1
mp 124-125 oC; H NMR (300 MHz, CDCl3): δ = 8.41 (br s, 1 H), 7.65 %; Pale yellow solid; m.p. 142-144 oC; 1H NMR (400 MHz, DMSO-d6)
(d, 1 H, J = 8.0 Hz), 7.50 (d, 1 H, J = 2.5 Hz), 7.46 (d, 1 H, J = 8.0 Hz), δ = 8.49 (br s, 1 H), 7.71 (s, 1 H), 7.49 (d, 1 H, J = 2.4 Hz), 7.36 (d, J =
7.30 (t, 1 H), 7.20 (t, 1 H), 7.06 (d, 2 H, J = 8.0 Hz), 7.02 (d, 2 H, J = 8.4, 1 H), 7.33 (d, J = 8.4, 1 H), 7.14 (d, J = 8.4, 2 H), 7.0 (d, J = 8.4 Hz,
8.0 Hz), 2.27 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ = 136.3, 135.3, 2 H); 13C NMR (125 MHz, CDCl3): δ = 137.4, 135.3, 132, 131, 130.8,
134.5, 130.3, 129.3, 128.9, 126.1, 122.8, 120.7, 119.5, 111.4, 20.7; 129, 127.2, 126.4, 122.2, 114.8, 113.3, 102.5; Anal. Calcd. for
Anal. Calcd. for C15H13NS: C, 75.28; H, 5.47; N, 5.85 %; found: C, C14H9BrClNS: C, 49.65; H, 2.68; N, 4.14 %; found: C, 49.67; H, 2.69;
75.27; H, 5.48; N, 5.84 %.
N, 4.17 %.
3-[(4-Chlorophenyl)thio]-1H-indole (3c).15 119 mg, Yield: 92 %; 5-Bromo-3-(p-bromophenylthio)-1H-indole (3j).10h 167 mg, Yield:
1
White solid; m.p. 126-127 oC; H NMR (400 MHz, CDCl3): δ = 8.43 87 %; Pale yellow solid; m.p. 156-158 oC; 1H NMR (400 MHz, DMSO-
(br s, 1 H), 7.62 (d, J = 7.6 Hz, 1 H), 7.50-7.46 (m, 2 H), 7.34 (t, J = 7.2 d6): δ = 11.93 (br s, 1 H), 7.83 (d, J = 2.3 Hz, 1 H), 7.45 (d, J = 8.7 Hz,
Hz, 1 H), 7.23 (t, J = 7.2 Hz, 1 H), 7.16 (d, J = 7.6 Hz, 2 H), 7.06 (d, J = 2 H), 7.37 (d, J = 8.7 Hz, 2H ), 7.29-7.26 (m, 1 H), 6.91 (d, J = 8.7 Hz, 2
7.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ = 137.7, 136.4, 130.6, H); Anal. Calcd. for C14H9Br2NS: C, 43.89; H, 2.37; N, 3.66 %; found:
130.4, 128.69, 128.65, 126.9, 123.1, 120.9, 119.4, 111.5, 102.2; C, 43.86; H, 2.35; N, 3.68 %.
Anal. Calcd. for: C14H10ClNS: C, 64.73; H, 3.88; N, 5.39 %; found: C,
64.71; H, 3.87; N, 5.40 %.
5-Bromo-3-(phenylthio)-1H-indole (3k).15 140 mg, Yield: 92 %;
White solid; m.p. 120–122 C; H NMR (400 MHz, DMSO-d6): δ =
o
1
3-[(4-Bromophenyl)thio]-1H-indole (3d).15 141 mg, Yield: 93 %; 11.88 (br s, 1 H), 7.81 (d, J = 2.8 Hz, 1 H), 7.50-7.42 (m, 2 H), 7.28–
1
White solid; mp 145-147 oC; H NMR (400 MHz, CDCl3): δ = 8.46 (br 7.25 (m, 1 H), 7.17 (t, 2H), 7.06-7.02 (m, 1 H), 6.98-6.96 (m, 2 H); 13
C
s, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), 7.48 (d, J = NMR (125 MHz, CDCl3): δ = 138.9, 136.2, 133.9, 131.3, 129, 128.7,
7.6 Hz, 1 H), 7.33-7.28 (m, 3 H), 7.23 (t, J = 7.6 Hz, 1 H), 6.99 (d, J = 126.3, 120, 119.4, 115, 111, 99.1; Anal. Calcd. for C14H10BrNS: C,
7.6 Hz, 2 H); 13C NMR (125 MHz, CDCl3): δ = 138.4, 136.3, 131.5, 55.28; H, 3.31; N, 4.60 %; found: C, 55.31; H, 3.33; N, 4.63 %.
130.6, 128.6, 127.2, 123.1, 120.9, 119.4, 118.1, 111.5, 102.1; Anal.
Calcd. for C14H10BrNS: C, 55.28; H, 3.31; N, 4.60 %; found: C, 55.26; 5-Methoxy-3-(phenylthio)-1H-indole (3l).9d 124 mg, Yield: 97 %;
1
H, 3.33; N, 4.61 %.
Colorless crystals; m.p. 77-79oC; H NMR (400 MHz, DMSO-d6) δ =
11.94 (br s, 1 H), 7.83 (s, 1H), 7.45-7.43 (m, 2 H), 7.28–7.19 (m, 3 H),
3-[(4-Nitrophenyl)thio]-1H-indole (3e).15 119 mg, Yield: 88 %; 6.97-6.95 (m, 2 H), 3.74 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ = 155,
1
Yellow solid; mp 177-178oC; H NMR (500 MHz, CDCl3): δ = 8.65 (br 139.2, 131.2, 129.8, 129.2, 128.6, 125.6, 124.6, 113.4, 112.3, 101.9,
s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H), 7.57-7.52 (m, 3 H), 7.36 (t, J = 7.6 Hz 100.8, 55.6; Anal. Calcd. for C15H13NOS: C, 70.56; H, 5.13; N, 5.49 %;
1 H), 7.24 (t, J = 7.6 Hz 1 H), 7.16 (d, J = 8.8 Hz, 2 H); 13C NMR (125 found: C, 70.59; H, 5.15; N, 5.47 %.
MHz, CDCl3): δ = 149.6, 143.0, 136.4, 134.0, 131.0, 124.9, 123.7,
123.4, 121.3, 119.1, 111.8, 100.4; Anal. Calcd. for C14H10N2O2S: C, 5-Nitro-3-(phenylthio)-1H-indole (3m).15 81 mg, Yield: 72 %; Yellow
62.21; H, 3.73; N, 10.36 %; found: C, 62.23; H, 3.76; N, 10.35 %.
solid; m.p. 151–154 oC; 1H NMR (400 MHz, D2O): δ = 8.76 (br s, 1 H),
8.63 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 8 Hz, 2 H), 7.47 (d. J
3-[(2-Nitrophenyl)thio]-1H-indole (3f). 115 mg, Yield: 85 %; White = 9.2 Hz, 1 H), 7.40 (s, 1 H), 7.34 (t, J = 7.6 Hz, 2 H), 7.28–7.23 (m, 1
o
1
solid; m.p. 155–157 C; H NMR (400 MHz, CDCl3): δ = 8.86 (br s, 1 H); 13C NMR (125 MHz, CDCl3): δ = 143.6, 143.1, 138.4, 134.6, 131.1,
H), 8.33 (d, J = 8 Hz, 1 H), 7.50 (t, J = 8 Hz, 2 H), 7.30–7.14 (m, 5 H), 129.2, 128.1, 125.1, 116.1, 114.9, 111.6, 99.7; Anal. Calcd. for
6.82 (d, J = 8 Hz, 1 H); Anal. Calcd. for C14H10N2O2S: C, 62.21; H, 3.73; C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36 %; found: C, 62.23; H, 3.70;
N, 10.36 %; found: C, 62.20; H, 3.71; N, 10.37 %.
N, 10.37 %.
3-[(2-naphthyl)thio]-1H-indole (3g).15 132 mg, Yield: 96 %; White 2-Methyl-3-(p-tolylthio)-1H-indole (3n).9d 120 mg, Yield: 95 %;
o
1
solid; m.p. 141–142 C; H NMR (400 MHz, CDCl3): δ = 8.47 (br s, 1 White solid; m.p. 97-99 oC; 1H NMR (400 MHz, CDCl3): δ = 8.25 (br s,
H), 7.76 (d, J = 7.6 Hz, 1 H), 7.68 (t, J = 8.8 Hz, 2 H), 7.60-7.48 (m, 4 1 H), 7.59 (d, J = 7.6 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.23 (t, J = 7.2
H), 7.42–7.35 (m, 2 H), 7.31–7.28 (m, 2 H), 7.19 (t, J = 7.2 Hz, 1 H); Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.01-6.93 (m, 4 H), 2.54 (s, 3 H),
13C NMR (100 MHz, CDCl3) δ = 136.5, 136.4, 133.6, 131.2, 130.6, 2.27 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ = 136.8, 135.5, 135.2,
128.9, 128.1, 127.5, 126.8, 126.2, 124.9, 124.6, 123.4, 122.9, 120.8, 134.1, 130.2, 129.3, 125.6, 121.9, 120.4, 118.8, 111.2, 103, 20.7, 12;
119.6, 111.4, 102.7; Anal. Calcd. for C18H13NS: C, 78.51; H, 4.76; N, Anal. Calcd. for C16H15NS: C, 75.85; H, 5.97; N, 5.53 %; found: C,
5.09 %; found: C, 78.53; H, 4.75; N, 5.07 %.
75.82; H, 5.98; N, 5.54 %.
2-Methyl-3-(phenylthio)-1H-indole (3h).15 108 mg, Yield: 90 %; 1-Methyl-3-(phenylthio)-1H-indole (3q).9d 114 mg, Yield: 95 %;
1
White solid; mp 109-110 oC; H NMR (600 MHz, CDCl3): δ = 8.28 (br White solid; mp 109-110 oC; 1H NMR (400 MHz, DMSO-d6): δ = 7.31
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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RSC Advances
Page 6 of 8
ARTICLE
Journal Name
8
9
(a) P. Hamel, J. Org. Chem., 2002, 67, 2854; (b) M. Raban and
(d, J = 8.0 Hz, 2 H), 7.14 (t, J = 7.7 Hz, 2 H), 7.09-6.95 (m, 4 H), 6.81
(d, J = 7.7 Hz, 2 H), 2.40 (s, 3 H); Anal. Calcd. for C15H13NS: C, 75.28;
H, 5.47; N, 5.85 %. Found: C, 75.26; H, 5.48; N, 5.84 %.
View Article Online
L.-J. Chern, J. Org. Chem., 1980, 45, 1688.
DOI: 10.1039/C5RA26425A
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Famiglini, F. Piscitelli and R. Silvestri, ACS Comb. Sci., 2012,
14, 258; (c) W. Ge and Y. Wei, Synthesis, 2012, 934; (d) W. Ge
and Y. Wei, Green Chem., 2012, 14, 2066; (e) Z. Li, J. Hong
and X. Zhou, Tetrahedron, 2011, 67, 3690; (f ) X.-L. Fang, R.-Y.
Tang, P. Zhong and J.-H. Li, Synthesis, 2009, 4183; (g) C. C.
Browder, M. O. Mitchell, R. L. Smith and G. el-Stdayman,
Tetrahedron Lett., 1993, 34, 6245; (h) P. Sang, Z. Chen, J.
Zoua, and Y. Zhang, Green Chem., 2013, 15, 2096. (g) Ch. D.
Prasad, S. Kumar, M. Sattar, A. Adhikary and S. Kumar, Org.
Biomol. Chem., 2013, 11, 8096; (h) Y. Liu, H. Wang, C. Wang,
3-Methyl-2-(phenylthio)-1H-indole (4a).9d 115 mg, Yield: 96 %;
o
1
White solid; mp 76-78 C; H NMR (400 MHz, CDCl3): δ = 8.24 (br s,
1 H), 7.60 (d, J = 8 Hz, 1 H), 7.38 (d, J = 8 Hz, 1 H), 7.23-7.17 (m, 4 H),
7.09 (d, J = 7.2 Hz, 1 H), 2.44 (s, 3H); Anal. Calcd. for C15H13NS: C:
75.28; H: 5.47; N: 5.85 %. Found: C, 75.29; H, 5.46; N, 5.86 %.
1
Bis(phenyl)disulfide (5a). Yield: 95 %; White solid; mp 59-61 oC; H
NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 4 H), 7.45 (d, J = 8.0
Hz, 4 H), 7.13 (t, J = 8.0 Hz, 2 H);13C NMR (100 MHz, CDCl3) δ =
136.6, 130, 129.2, 125; Anal. Calcd. for C12H10S2: C, 66.01; H,4.62.
Found: C, 66.04; H, 4.60 %.
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Acknowledgements
The authors are thankful to the Director, NIT Silchar for financial
support. MHRD is also acknowledged for the doctorate fellowship
received by R.F.R and N.D.
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View Article Online
DOI: 10.1039/C5RA26425A
Microwave-assisted regioselective sulfenylation of indoles under
solvent- and metal-free conditions
Rajjakfur Rahaman, Namita Devi, Jyoti Rekha Bhagawati and Pranjit Barman*
R2
N
R1
R2
0.5 mmol
+
R
S
n-Bu4NI (0.6 mmol), TsOH (0.2 mmol
R2
or
S
MW (110 W), 10 min, 70 o
C
N
R1
N
R1
R
RSO2H
"SOLVENT FREE"
0.6 mmol
20 examples
up to 97 % yield
R = aryl, alkyl, naphthyl; R1 = H, Me; R2 = H, Br, OMe, NO2
Formation of 3-sulfenylindoles using sulfinic acid as a sulfenylating agent