Metal- and base-free syntheses of aryl/alkylthioindoles by the iodine-induced reductive coupling of aryl/alkyl sulfonyl chlorides with indoles

Article abstract of DOI:10.1039/c5ra00646e

An Iodine-catalysed process for an efficient and scalable sulfenylation protocol for indoles employing aryl-/alkyl sulfonyl chlorides has been developed. A series of sterically and electronically divergent aryl-/alkyl sulfonyl chlorides participated in th

Full text of DOI:10.1039/c5ra00646e

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ARTICLE
Metal- and base-free syntheses of aryl /
alkylthioindoles by the iodine-induced reductive
Cite this: DOI: 10.1039/x0xx00000x
coupling of aryl / alkyl sulfonyl chlorides with indoles
Gullapalli Kumaraswamy *(a,b) Ragam Raju(a) and Vykunthapu Narayanarao(a)
Received 00th January 2012,
Accepted 00th January 2012
Abstract An Iodineꢀcatalysing process for an efficient and scalable sulfenylation protocol for indoles
employing arylꢀ/ alkyl sulfonyl chlorides has been developed. A series of sterically and electronically
divergent arylꢀ/ alkyl sulfonyl chlorides were participated in the sulfenylation of C(sp2)ꢀH bonds,
resulting in a high to excellent yield of indole 3ꢀsulfenylether molecules. It is noteworthy that indoleꢀ3ꢀ
thiomethyl ether is efficiently generated with methanesulfonyl chloride as an electrophile, indicating the
potential of this methodology.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Indole sulfenylether molecules are the basic motif of
numerous pharmaceutically active molecules due to their
inherent potential biological activity.1 They are also important
precursors of functional materials that enable the realisation of
novel properties.2 The critical importance of these scaffolds has
resulted in the development of various synthetic methods. Thus
far sulfenylating agents for the thiolation of C(sp2)ꢀH bonds
have included disulfides,3 sodium sulfinates,4 sulfenyl halides,5
N
ꢀthioarylphthalimides,6 and sulfonyl hydrazides,7 catalyzed by
metalꢀfree salts such as iodine or metal salts (Scheme 1). In
spite of the availability of various thiolating agents8 for the
sulfenylation of indole C(sp2)ꢀH bonds, a limitation remains
with regard to accessing these precursors due to the multistep
synthesis process required. The thiolation can be achieved in
principle, by means of arylꢀ/ alkylꢀ/ heteroarylsulfonyl
chlorides as a sulphur source. Arylꢀ/ alkylꢀ/ heteroarylsulfonyl
chlorides are remarkably stable, inexpensive and mostly
commercially available. Fairly recently, arylꢀ/ alkylꢀ/
heteroarylsulfonyl chlorides9a as a sulphur source were assessed
by means of reductive coupling with indolizines, indoles,
electronꢀrich benzenes9b and Hꢀphosphonates.9c On the other
hand, visible lightꢀinduced sulfenylation of indoles and
Nꢀ
methylindoles with arylsulfonyl chlorides was also discovred.10
Scheme 1. Prior art in the sulfenylation of indole C(sp2)ꢀH
bonds.
Interestingly, in all cases an excess of one of the reactant is
essential for transformation to be observed, resulting in the
concomitant quantitative production of corresponding oxidizing
substrate as a byꢀproduct.11 Furthermore, sulfonyl chlorides
Previous work:
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DOI: 10.1039/C5RA00646E
have been employed in excess to improve the yields of equiv. of 1a and 1.0 equiv. of 2a improved the yield of the
corresponding sulfenylether molecules.
desired product (Table 1, entries 2 and 3, respectively). Loading
1.0 equiv. of 1a and 2.0 equiv. of 2a13 furnished a lower yield
of 3a (Table 1, entry 4). The screening of various solvents
indicated that 1,4ꢀdioxane is the only preferable medium for
this transformation (Table 1, entries 3 and 6ꢀ9).
Results and discussion
With our continued interest in developing a copperꢀ
catalysed sulfenylation process,12 herein we describe our
finding regarding the synthesis of aryl / alkylthioindoles by the
iodineꢀinduced reductive coupling of aryl / alkyl sulfonyl
chlorides with indoles.
Table 2. Scope of sulfenylation with the functional group substituted
indoles and arylꢀ alkyl sulfonyl chlorides.a
Table 1. Evaluation of optimized conditions for the synthesis of 3ꢀ(
pꢀ
tolyl)thioindole a
.
1a
2a
3a
Entry
R1
R2
R3
Time % yieldb
(h)
entry
catalyst
(10 mol%)
solvent
3a
(% yield)e
64
1
2
3
4
H
H
H
H
H
H
H
H
Ph
4
4
4
3
3b, 85
3c, 85
3d, 81
3e, 78
1
2
3
4
5
6
7
8
9
10
11
12
13
CuI
I2
I2
I2
I2
I2
I2
I2
dioxane
dioxane
dioxane
dioxane
dioxane
CH3CN
DMF
(CH2Cl2)2
DMSO
dioxane
dioxane
dioxane
dioxane
2,5ꢀMeꢀPh
4ꢀClꢀPh
3,5ꢀClꢀ4ꢀ
MeꢀPh
4ꢀBrꢀPh
5ꢀFꢀ2ꢀMeꢀ
Ph
54b
86c,g
65d
60f
64
40
30
15
40
5
6
H
H
H
H
4
3
3f, 80
3g, 77
I2
(nꢀBu)4NI
7
8
9
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
3ꢀCF3ꢀPh
4ꢀIꢀPh
2
4
4
1.5
1
3
3
3
4
3
3h, 77
3i, 82
3j, 75
3k, 76
3l, 72
3m, 84
3n, 82
3o, 87
3p, 76
3q, 72
3r, 71
NRc
KI
ICl
Nꢀ
20
82
72
4ꢀMeꢀPh
3ꢀNO2ꢀPh
4ꢀNO2ꢀPh
4ꢀMeꢀPh
4ꢀMeꢀPh
4ꢀMeꢀPh
Bn
iodosuccinimide
10
11
12
13
14
15
16
17
18
19
H
a) All reactions were carried out unless otherwise stated on
the 1 mmol scale using 2 mmol of 1a and 1 mmol of 2a
in 3 ml of dioxane heated to 80 ℃ for 4 h in open air.
b) The reaction was carried out with 1.0 equiv. 1a and 1.1
equiv. of 2a.
c) The reaction was carried out with 2.0 equiv. 1a and 1.0
equiv. of 2a.
5ꢀBromo
5ꢀIodo
5ꢀMethoxy
H
H
H
5ꢀCN
H
Me
d) The reaction was carried out with 1.0 equiv. 1a and 2.0
equiv. of 2a.
H
H
Ts
n
ꢀBu
3
4
4
e) Isolated yield, but not optimized. Yields based on the
disappearance of 2a.
4ꢀMeꢀPh
4ꢀMeꢀPh
NRc
f)
The reaction was carried out with 5 mol% of catalyst at
80 ℃.
g) This reaction was also carried out at 10 mmol scale.
a) All reactions were carried out on the 2 mmol scale using 1a-1g (2.0
equiv.), 2a-n (1.0 equiv.), I2 (10 mol%) in dioxane heated at 80 ℃ in
open air.
b) Isolated yield, but not optimized.
Initially, we chose indole 1a and pꢀtoluenesulfonyl chloride 2a
c) NR = No reaction.
as the test substrates. At the outset, in the presence of 10 mol%
of CuI in dioxane 1a (1.0 equiv.) and 2a (1.1 equiv.) reacted
smoothly at 80 °C for 4h to afford the expected 3ꢀ(pꢀ
tolyl)thioindole 3a at a 64% yield (Table 1, entry 1). As we
intended to develop a metalꢀfree sulfenylation process, we
replaced CuI with iodine. With 10 mol% of I2, the same
reaction under otherwise identical conditions resulted in 3a at a
55% isolated yield (Table 1, entry 2). Under typical conditions,
the molar ratios of reactants have shown considerable influence
on the product yield (3a). Using 1.0 equiv. of 1a and 1.1 equiv.
of 2a yielded the desired product at 55%, whereas, loading 2.0
In a brief survey of an alternative source of iodine applied as a
catalyst, the yield of 3a decreased (Table 1, entry 2). Further,
when the reaction was conducted under strict anaerobic
conditions, only a trace amount of 3a was isolated (Table 1,
entry 10ꢀ13). The reaction carried out with 5 mol% of iodine
resulted in 3a at an inferior yield (Table 1, entry 5).
With the optimal conditions in hand, the scope of the substrate
was surveyed. These results are shown in Table 2.
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(Table 2, entry 11, and 12). Further, the haloꢀcontaining
coupled product of arylthioindoles facilitates potential
applications of further functionalization by a crossꢀcoupling
reaction. Remarkably, 3ꢀNO2ꢀ, and 4ꢀNO2ꢀsubstituted
phenylsulfonyl chlorides remain viable in this protocol
disregarding the electronic effects and furnishing the desired
products of 3k and 3l at high yields (Table 2, entries 10 and
11). 2ꢀnitrobenzenesulfonyl chloride was also reacted with
indole, but the effort to isolate the product which formed failed
Table 3. Further scope of the sulfenylation reaction.a
Arylsulfonyl chloride
product
% yieldb
due to rapid decomposition. Under set conditions,
Nꢀ
methylindole was also an effective substrate for coupling with
2a to give the sulfenylation product 3j at a high yield (Table 2,
76
entry 9), but the
coupling reaction (Table 2, entry 19).
Nꢀtosyl protected indole did not undergo a
2a
5a
Next, we examined the alkyl sulfonyl chlorides, as these
compounds are seldom employed due to their inherent reduced
reactivity and rapid decomposition. To our delight, our method
gave 3ꢀalkylthioethers 3q and 3r at a good yield using
methanesulfonyl chloride 2m and butanesulfonyl chloride 2n
with 1a (Table 2, entries 16 and 17). 2ꢀMethylindole 4a was
64
2aa
2aa
5b
also reacted with pꢀtoluenesulfonyl chloride 2a under typical
conditions and gave the corresponding 3ꢀthioether 5a at a high
yield (72%). It was gratifying to find a reaction between the
1,3ꢀbenzenedisulfonyl chloride 2aa with 1a (2 equiv), that
provided an acceptable yield (64%) of monoꢀindolylsulfenyl
ether 5b. on the other hand, when 2aa treated with 4 equiv of
1a, diꢀindolylsulfenyl ether 5c was formed at a high yield
(78%) (Table 3). Significantly, a highly polar carboxylic acid
substituted arylsulfonylchloride 2ab performed well with 1a
and 1b under the standard protocol, affording carboxylic acid
possessing thioindole 5d and 5e at an 81% and 84% yield,
respectively (Table 3). Several control experiments were
78
81
5c
2ab
2ab
5d
carried out to understand this transformation. Indole 1a and pꢀ
toluenesulfonyl chloride 2a was heated to 80 °C for 4h. No
trace of the desired product 3a was observed and only the
starting materials were recovered. In another experiment, with
10 mol% of iodine, one equiv. each of 1a and 2a were
individually reacted under optimized conditions. In both cases,
the recovery of the starting materials was realized, indicating
the necessity of all reaction partners in order to forward the
reaction. The reaction of 1a and 2a with one equivalent of
TEMPO under standard protocol resulted in 3a as exclusive
product and no trace of TEMPOꢀcoupled products were
observed suggesting ionic mechanism rather than radical
mechanism.
84
5e
a) All reactions were carried out on the 2 mmol scale using 1a,
1b and 4a (2.0 equiv.), 2a, 2aa and 2ab (1.0 equiv.), I2 (10
mol%) in dioxane heated at 80 ℃ in open air.
b) Isolated yield, but not optimized.
Considering the above results, a plausible reaction mechanism
is delineated in Scheme 2, which will clearly require further
experimentation. Initially, iodine induced substitution of
chlorine atom of arylꢀ / alkyl sulfonyl chloride leads to putative
According to the results, the electronꢀdonating and electron–
withdrawing functional groups on the phenyl ring of sulfonyl
chloride were compatible under the standard protocol and
reacted with equal efficiency. On the other hand, the reaction
efficiency was slightly sensitive to the electronic properties of
the indole moiety. For instance, 5ꢀcyanoindole failed to give the
expected sulfenylation product, while 5ꢀbromoꢀ and 5ꢀ
iodoindole did react under these conditions providing the
desired product 3m and 3n, respectively at a very good yield,
intermediate [
FriedelꢀCrafts reaction of indole with [
A
] by eliminating ICl.14
Then, subsequent
] followed by HI
A
exclusion via aromatization afford sulfone [D], which can
undergo deoxygenation in the presence of HI to afford the
desired indolylsulfenyl ether. Eventually, HOI can be oxidized
in the presence of air to give I2 and H2O2 (Scheme 3).
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Column chromatography was carried out using Silica gel 100ꢀ200
mesh (commercial suppliers).
Scheme 2. Plausible mechanism for the observed transformation.
The typical procedure for synthesis of 3-(p-Tolylthio)-1H-indole
(3a): To a stirred solution of indole 1a (2 mmol) in 1,4ꢀdioxane (3
mL) was added sulfonylchloride, 2a (1.0 mmol) and I2 (10 mol%)
successively. The resulting reaction mixture was heated at 80 ℃ for
4 h in open air. Subsequently, the reaction mixture was cooled down
to ambient temperature, and the solvent was evaporated under
reduced pressure. The resulting residue was purified by silica gel
chromatography, eluting with hexane / ethyl acetate (10:0.5 to 5:1)
to give the thioindole, 3a at an 86% yield. White solid, Yield – 206
mg (86%), m.p. 124ꢀ126 ℃; 1H-NMR (500 MHz, CDCl3): δ 8.38 (s,
br, 1H), 7.61 (d, J = 7.93 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.27 – 7.24
(m, 1H), 7.17 – 7.14 (m, 1H), 7.04 – 6.96 (m, 4H), 2.25 (s, 3H);
13C-NMR (75 MHz, CDCl3): δ 136.4, 135.4, 134.6, 130.4, 129.4,
129.1, 126.2, 122.9, 120.8, 119.7, 111.5, 103.5, 20.8; IR (neat, cmꢀ
1): 3405, 2922, 2853, 1892, 1490, 1453, 1088, 772, 744; HRMS
(m/z): Calculated for C15 H13 N S (MꢀH) = 239.0768 found (MꢀH) =
239.0775.
All other 3ꢀaryl and alkyl thioindole were prepared employing above
typical procedure.
3-(Phenylthio)-1H-indole (3b): White solid, m.p. 150ꢀ152 ℃;
1
Yield ꢀ 191 mg (85%); H-NMR (500 MHz, CDCl3): δ 8.47 (s, br,
1H), 7.61 (d, J = 7.9 Hz,1H), 7.49 – 7.43 (m, 2H), 7.28 – 7.25 (m,
1H), 7.18 – 7.03 (m, 6H); 13C-NMR (75 MHz, CDCl3): δ 139.2,
130.7, 128.6, 125.8, 124.7, 123.0, 120.9, 119.6, 111.5; IR (neat, cmꢀ
1): 3401, 3057, 2922, 2852, 1580, 1476, 1234, 1083, 770, 739;
HRMS (m/z): Calculated for: C14 H11 N S (M+K) = 264.0249, found
(M+K) = 264.0238.
Conclusions
3-((2,5-Dimethylphenyl)thio)-1H-indole (3c): White solid, m.p.
1
125ꢀ127 ℃; Yield ꢀ 215 mg (85%); H-NMR (500 MHz, CDCl3): δ
In conclusion, we have demonstrated an efficient crossꢀ
coupling reaction of indole with lowꢀcost, and readily available,
stable arylꢀ / alkyl sulfonyl chlorides through C(sp2)ꢀH bond
activation for the syntheses of various 3ꢀalkylꢀ/ arylthioethers.
The sulfenylation process is initiated by a catalytic amount of I2
without any combination of radical initiator. This process is
8.42 (s, br, 1H), 7.63 – 7.57 (m, 1H), 7.45 – 7.40 (m, 2H), 7.29 –
7.23 (m, 1H), 7.19 – 7.13 (m, 1H), 7.04 – 6.99 (m, 1H), 6.82 – 6.75
(m, 1H), 6.57 (s, 1H), 2.46 (s, 3H), 2.04 (s, 3H); 13C-NMR (125
MHz, CDCl3): δ 137.7, 136.5, 135.8, 131.4, 130.7, 129.7,129.2,
125.9, 125.4, 122.9, 120.7, 119.7, 111.5, 102.4, 21.0, 19.4; IR (neat,
cmꢀ1): 3412, 2926, 2857, 1896, 1520, 1456, 1075, 778, 734; HRMS
remarkable in that stoichiometric reducing trivalent (m/z): Calculated for C16 H15 N S (MꢀH) = 252.0842, found (MꢀH)
= 252.0846.
phosphorous compounds are avoided. To the best of our
knowledge, this is the first report on sulfenylation wherein
catalytic iodine acts as a reducing agent in combination with air
and avoids the creation of oxides of phosphorous. Further work
is in progress to broaden the scope of this methodology.
3-(4-Chlorophenylthio)-1H-indole (3d): White solid, m.p. 129ꢀ131
1
℃; Yield ꢀ 210 mg (84%); H-NMR (500 MHz, CDCl3): δ 8.42 (s,
br, 1H), 7.56 (dd, J = 7.93 Hz, J = 0.76 Hz, 1H), 7.46 (d, J = 2.59
Hz, 1H), 7.43 (d, J = 8.24 Hz, 1H),7.29 – 7.24 (m, 1H), 7.18 – 7.15
(m, 1H), 7.12 – 7.09 (m, 2H), 7.02 – 6.99 (m, 2H); 13C-NMR (75
MHz, CDCl3): δ 137.8, 136.5, 130.7, 130.5, 128.7, 127.1, 123.2,
121.0, 119.5, 111.6, 102.4; IR (neat, cmꢀ1): 3405, 2921, 2851, 1472,
1090, 1008, 812, 746; HRMS (m/z): Calculated for: C14 H9 N S Cl
(MꢀH) = 258.0144, found (MꢀH) = 258.0150.
Acknowledgements
Financial support was provided by the DST, New Delhi, India
(Grant No: SR/S1/OCꢀ08/2011), ORGIN (CSCꢀ0108) programme
CSIR (New Delhi) of XII Five year plan is gratefully acknowledged.
Also, UGC & CSIR (New Delhi) is acknowledged for awarding the
fellowships to R.R. and V.N.R.
3-((3,5-Dichloro-4-methylphenyl)thio)-1H-indole (3e): White
solid, m.p. 142ꢀ145 ℃; Yield ꢀ 239 mg (84%); 1H-NMR (500 MHz,
CDCl3): δ 8.51 (s, br, 1H), 7.58 – 7.45 (m, 3H), 7.34 – 7.27 (m, 1H),
7.22 – 7.15 (m, 1H), 6.93 (d, J = 8.51 Hz, 1H), 6.41 (d, J = 8.71 Hz,
1H), 2.50 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 137.8, 136.6,
134.5, 131.3, 131.0, 130.7, 128.8, 127.3, 123.9, 123.3, 121.2, 119.5,
111.7, 101.3, 17.7; IR (neat, cmꢀ1): 3405, 2923, 2863, 1894, 1488,
1463, 1091, 774; HRMS (m/z): Calculated for C15 H10 N Cl2 S (Mꢀ
H) = 305.9906, found (MꢀH) = 305.9921.
Experimental section
General procedure
:
spectra were recorded at 300, 400 & 500 MHz, and 13C NMR 75 &
125 MHz in CDCl3. The J values were recorded in hertz and
abbreviations used were as follows: sꢀsinglet, dꢀdoublet, mꢀmultiplet,
brꢀbroad, ddꢀdoublet of doublet. Chemical shifts (δ) are reported
relative to TMS (δ = 0.0) as an internal standard. The IR (FTꢀIR)
spectra were measured using KBr pellet or as film. Mass spectral
data were compiled using MS (ESI), HRMS mass spectrometers.
3-(4-Bromophenylthio)-1H-indole (3f): White solid, m.p. 141ꢀ143
1
℃; Yield ꢀ 242 mg (80%); H-NMR (500 MHz, CDCl3): δ 8.47 (s,
br, 1H), 7.56 (d, J = 7.93 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.30 – 7.15
(m, 4H), 6.97 – 6.93 (m, 2H); 13C-NMR (75 MHz, CDCl3): δ 138.5,
136.5, 131.6, 130.7, 128.7, 127.3, 123.2, 121.0, 119.4, 118.2, 111.7,
102.1; IR (neat, cmꢀ1): 3389, 3053, 2921, 2851, 1889, 1469, 1406,
1235, 1083, 1004, 808, 744; HRMS (m/z): Calculated for C14 H9 N
S Br (MꢀH) = 301.9639, found (MꢀH) = 301.9645.
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3-((5-fluoro-2-methylphenyl)thio)-1H-indole (3g): White solid, br, 1H), 7.51 (dd, J = 6.9 Hz, J = 1.7 Hz, 1H), 7.43 (d, J = 2.6 Hz,
m.p. 136ꢀ138 ℃; Yield ꢀ 198 mg (77%); 1H-NMR (500 MHz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.0 (s, 4H), 2.26 (s, 3H); 13C-NMR
CDCl3): δ 8.44 (s, br, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 2.6 (75 MHz, CDCl3): δ 135.5, 134.9, 134.8, 131.6, 131.4, 131.2, 129.6,
Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.30 – 7.24 (m, 2H), 7.20 – 7.16 128.4, 126.2, 113.5, 102.9, 84.7, 20.8; IR (neat, cmꢀ1): 3645, 2924,
(m,1H), 6.85 – 6.79 (m, 1H), 6.64 – 6.59 (m, 1H), 2.06 (s, 3H); 13C- 2853, 1692, 1512, 1453, 1098, 772, 646; HRMS (m/z): Calculated
NMR (125 MHz, CDCl3): δ 157.6 (d, JCꢀF = 241.6 Hz), 136.4, 133.8 for C15 H11 N I S (MꢀH) = 363.9651, found (MꢀH) = 363.9665.
(d, JCꢀF = 2.7 Hz), 131.0, 129.2, 128.5, 127.0 (d, JCꢀF = 7.3 Hz),
125.6 (d, JCꢀF = 16.4 Hz), 123.1, 120.9, 119.5, 114.8 (d, JCꢀF = 21.8
5-methoxy-3-(p-tolylthio)-1H-indole (3o): Brown oil; Yield ꢀ 234
Hz), 111.6, 101.1, 20.7; IR (neat, cmꢀ1): 3412, 2934, 2863, 1882,
1492, 1453, 1168, 764; HRMS (m/z): Calculated for C15 H12 F N S
(MꢀH) = 256.0590, found (MꢀH) = 256.0592.
mg (87%); 1H-NMR (500 MHz, CDCl3): δ 8.31 (s, br, 1H), 7.35 (d,
J = 2.7 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H),
7.03 – 6.99 (m, 2H), 6.98 – 6.95 (m, 2H), 3.76 (s, 3H), 2.23 (s, 3H);
13C-NMR (125 MHz, CDCl3): δ 155.0, 135.6, 134.5, 131.3, 131.1,
3-((3-(Trifluoromethyl)phenyl)thio)-1H-indole (3h): White solid, 129.9, 129.4,125.9, 113.5, 112.3, 102.7, 100.8, 55.7, 20.8; IR (neat,
m.p. 130ꢀ132 ℃; Yield ꢀ 226 mg (77%); 1H-NMR (500 MHz, cmꢀ1): 3455, 2923, 2893, 1887, 1495, 1463, 1296, 1098, 772, 744;
CDCl3): δ 8.47 (s, br, 1H), 7.57 (d, J = 7.93 Hz, 1H), 7.49 (d, J = HRMS (m/z): Calculated for C15 H13 N S (MꢀH) = 253.0556, found
2.59 Hz, 1H), 7.44 (d, J = 8.24 Hz, 1H), 7.39 (s, 1H), 7.30 – 7.26 (m, (MꢀH) = 253.0561.
2H), 7.24 – 7.15 (m, 3H); 13C-NMR (125 MHz, CDCl3): δ 140.9,
136.5, 131.0 (q, JCꢀF = 31.8 Hz), 130.9, 129.0, 128.7, 123.8 (q, JCꢀF
=
3-(Benzylthio)-1H-indole (3p): Yellow solid, m.p. 81ꢀ82 ℃; Yield
1
272.5 Hz), 123.3, 122.3, (d, JCꢀF = 3.6 Hz), 121.4 (d, JCꢀF = 3.6 Hz),
121.1, 119.3, 111.7, 101.4; IR (neat, cmꢀ1); HRMS (m/z):
Calculated for C15 H10 F3 N S (MꢀH) = 292.0402, found (MꢀH) =
292.0411.
ꢀ 182 mg (76%); H-NMR (500 MHz, CDCl3): δ 8.39 (s, br, 1H),
7.72ꢀ7.67 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.25 – 7.14 (m, 5H),
7.10 – 7.04 (m, 2H), 6.95 (s, 1H), 3.85 (s, 2H); 13C-NMR (75 MHz,
CDCl3): δ 139.0, 136.2, 129.9, 129.2, 128.1, 126.7, 122.4, 120.3,
119.1, 111.5, 105.0,40.9; IR (neat, cmꢀ1): 3406, 2872, 1902, 1560,
3-((4-iodophenyl)thio)-1H-indole (3i): White solid, m.p. 135ꢀ137 1463, 1078, 736; ESI-MS (m/z): Calculated for C15 H13 N S = 239,
1
℃; Yield ꢀ 288 mg (82%); H-NMR (500 MHz, CDCl3): δ 8.44 (s, found (MꢀH) = 238.
br, 1H), 7.58 – 7.54 (m, 1H), 7.48 – 7.41 (m, 4H), 7.30 – 7.25 (m,
1H), 7.20 – 7.14 (m, 1H), 6.84 – 6.80 (m, 2H); 13C-NMR (125 MHz,
3-(Methylthio)-1H-indole (3q): Colorless oil; Yield ꢀ 117 mg
(72%); 1H-NMR (500 MHz, CDCl3): δ 8.21 (s, br, 1H), 7.77 (d, J =
CDCl3): δ 139.5, 137.5, 136.4, 130.7, 128.9, 127.6, 123.2, 121.0,
119.4, 111.6, 102.0, 88.9; IR (neat, cmꢀ1): 3312, 2876, 2753, 1882,
7.63 Hz, 1H), 7.36 (d, J = 8.10 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H),
7.26 – 7.18 (m, 2H), 2.37 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ
134.2, 129.2, 127.8, 122.9, 121.0, 1118.9, 110.7, 105.1, 19.0; IR
(neat, cmꢀ1): 3386, 2853, 1876, 1490, 1451, 1058, 776, 754; ESI-
1496, 1455, 1076, 994, 752; HRMS (m/z): Calculated for C14 H10
N
I S (MꢀH) = 349.9495, found (MꢀH) = 349.9494.
1-Methyl-3-(p-tolylthio)-1H-indole (3j): White solid, m.p. 86ꢀ88 MS (m/z): Calculated for C9 H9 N S = 163, found (MꢀH) = 162.
℃; Yield ꢀ 190 mg (83%); 1H-NMR (500 MHz, CDCl3): δ 7.46 (d, J
= 8.4 Hz, 2H), 7.26 – 7.21 (m, 5H), 7.14 (d, J = 8.1 Hz, 2H), 2.42
3-(Butylthio)-1H-indole (3r): Yellow oil; Yield ꢀ 145 mg (71%);
(s, 3H), 2.38 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 144.5, 142.0,
140.4, 136.5, 130.2, 129.3, 127.6, 124.6, 29.7, 21.5; IR (neat, cmꢀ1):
3412, 2946, 2845, 1894, 1490, 1463, 1088, 772;HRMS (m/z):
Calculated for C11 H18 O3 N S (M+H) = 253.0925, found (M+H) =
253.0931.
1H-NMR (500 MHz, CDCl3): δ 8.26 (s, br, 1H), 7.77 (d, J = 7.93
Hz, 1H), 7.47 – 7.42 (m, 2H), 7.27 – 7.24 (m, 1H), 7.17 – 7.14 (m,
1H), 7.04 – 6.96 (m, 4H), 2.25 (s, 3H); 13C-NMR (75 MHz, CDCl3):
δ IR (neat, cmꢀ1): 3345, 2934, 2835, 1876, 1478, 1433, 1068, 762,
745; HRMS (m/z): Calculated for C12 H14 N S (MꢀH) = 204.0842,
found (MꢀH) = 204.0844.
3-((3-Nitrophenyl)thio)-1H-indole (3k): White solid, m.p. 135ꢀ137
1
℃; Yield ꢀ 205 mg (84%); H-NMR (500 MHz, CDCl3): δ 8.57 (s,
2-methyl-3-(p-tolylthio)-1H-indole (5a): White solid, m.p. 93ꢀ96
1
br, 1H), 7.93 – 7.86 (m, 2H), 7.57 – 7.54 (m, 2H), 7.48 (d, J = 8.24
Hz, 1H), 7.36 (d, J = 7.93 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.21 – 7.16
(m, 1H); 13C-NMR (75 MHz, CDCl3): δ 136.4, 135.4, 134.6, 130.4,
129.4, 129.1, 126.2, 122.9, 120.8, 119.7, 111.5, 103.5, 20.8; IR
(neat, cmꢀ1): 3506, 2923, 2873, 1867, 1556, 1490, 1454 1353, 1088,
782, 762; HRMS (m/z): Calculated for C14 H9 O2 N2 S (MꢀH) =
269.0379, found (MꢀH) = 269.0390.
℃; Yield ꢀ 192 mg (76%); H-NMR (500 MHz, CDCl3): δ 8.21 (s,
br, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.19 –
7.15 (m, 1H), 7.13 – 7.09 (m, 1H), 6.95 (m, 4H), 2.49 (s, 3H), 2.23
(s, 3H); 13C-NMR (125 MHz, CDCl3): δ 140.9, 135.6, 135.3, 134.2,
130.2, 129.4, 125.7, 122.0, 120.5, 118.9, 110.6, 99.6, 20.8, 12.0; IR
(neat, cmꢀ1): 3415, 2892, 2763, 1952, 1560, 1463, 1078, 784, 753;
HRMS (m/z): Calculated for C15 H13 N S = 239.0768, found =
239.0775.
3-((4-nitrophenyl)thio)-1H-indole (3l): Yellow solid, m.p. 174ꢀ175
1
℃; Yield ꢀ 194 mg (84%); H-NMR (500 MHz, CDCl3): δ 8.92 (s,
3-((1H-indol-3-yl)thio)benzene-1-sulfonyl chloride (5b): White
solid, m.p. 156ꢀ159 ℃; Yield ꢀ 207 mg (64%); 1H-NMR (500 MHz,
CDCl3): δ 8.62 (s, br, 1H), 7.75 – 7.72 (m, 1H), 7.70 – 7.66 (m, 1H),
7.56 – 7.53 (m, 2H), 7.48 (d, J = 8.21 Hz, 1H), 7.36 – 7.28 (m, 3H),
7.21 – 7.17 (m, 1H); 13C-NMR (75 MHz, CDCl3): δ 144.7, 143.3,
136.5, 131.7, 131.2, 129.7, 128.3, 123.5, 123.2, 122.7, 121.4, 119.1,
111.9, 100.3; IR (neat, cmꢀ1): 3505, 3312, 2921, 2845, 1553, 1370,
1290, 1092, 776.
br, 1H), 7.95 (d, J = 9.0 Hz, 2H),7.52 – 7.46 (m, 3H), 7.28 (t, J = 8.1
Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H); 13C-
NMR (75 MHz, CDCl3): δ 150.0, 144.6, 136.5, 131.3, 128.3, 124.9,
123.7, 123.3, 121.2, 118.9, 112.0, 99.6; IR (neat, cmꢀ1): 3605, 3422,
2753, 1892, 1553, 1464, 1346, 1078, 784; ESI-MS (m/z): Calculated
for C14 H10 O2 N2 S = 270, found (MꢀH) = 269.
5-Bromo-3-(p-tolylthio)-1H-indole (3m): White solid, m.p. 126ꢀ
128 ℃; Yield
ꢀ
266 mg (84%); 1H-NMR (300 MHz,
1,3-bis((1H-indol-3-yl)thio)benzene (5c): White solid, m.p. 210ꢀ
212 ℃; Yield
ꢀ
290 mg (78%); 1H-NMR (300 MHz,
CDCl3+DMSO): δ 8.70 (s, br, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.42 (d,
J = 2.6 Hz, 1H), 7.32 – 7.29 (m, 1H), 7.26 – 7.24 (m, 1H), 7.01 –
6.96 (m, 4H), 2.25 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ 135.0,
134.8, 133.9, 132.1, 130.3, 128.8, 125.4, 124.4, 120.8, 113.1, 112.8,
100.5, 20.2; IR (neat, cmꢀ1): 3744, 3611, 2922, 2852, 1696, 1509,
1454, 1219, 772, 657; HRMS (m/z): Calculated for C15 H11 N S Br
(MꢀH) = 315.9795, found (MꢀH) = 315.9782.
CDCl3+DMSO): δ 10.84 (s, br, 2H), 7.56 (s, 2H), 7.50 – 7.43 (m,
2H), 7.36 (d, J = 2.5 Hz, 2H), 7.24 – 7.16 (m, 2H), 7.11 – 7.03 (m,
2H), 6.89 (t, J = 7.7 Hz, 1H), 6.83 – 6.79 (m, 1H), 6.72 – 6.66 (m,
2H); 13C-NMR (75 MHz, CDCl3+DMSO): δ 139.7, 136.1, 130.9,
128.2, 128.0, 121.7, 121.6, 121.3, 119.5, 118.2, 111.4, 99.5; IR
(neat, cmꢀ1): 3412, 2932, 2863, 1967, 1872, 1530, 1462, 1098, 792,
767; HRMS (m/z): Calculated for C22 H16 N2 S2 (M+H) = 373.0828,
5-iodo-3-(p-tolylthio)-1H-indole (3n): White solid, m.p. 132ꢀ134 found (M+H) = 373.0826.
1
℃; Yield ꢀ 299 mg (82%); H-NMR (500 MHz, CDCl3): δ 8.46 (s,
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

RSC Advances
Page 6 of 6
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA00646E
3-((1H-indol-3-yl)thio)benzoic acid (5d): White solid, m.p. 183ꢀ
186 ℃; Yield
218 mg (81%); 1H-NMR (300 MHz,
7. (a) F. –L. Yang, S. –K. Tian, Angew. Chem. Int. Ed. 2013, 52
,
ꢀ
4929; (b) X. Kang, R. Yan, G. Yu, X. Pang, X. Liu, L. Xiang,
G. Huang, J. Org. Chem. 2014, 79, 10605; (c) F. Xiao, H. Xie,
S. Liu, G.ꢀJ. Deng, Adv. Synth. Catal. 2014, 356, 364.
CDCl3+DMSO): δ 10.94 (s, br, 1H), 7.81 (s, 1H), 7.73 – 7.61 (m,
1H), 7.55 – 7.45 (m, 3H), 7.24 – 7.04 (m, 4H); 13C-NMR (75 MHz,
CDCl3+DMSO): δ 167.3, 139.7, 136.3, 131.2, 130.8, 129.1, 128.2,
127.9, 126.2, 125.4, 121.7, 119.6, 118.2, 111.6, 99.4; IR (neat, cmꢀ
1): 3402, 2978, 2876, 1887, 1753, 1492, 1443, 1068, 768, 744;
HRMS (m/z): Calculated for C15 H11 O2 N S (MꢀH) = 268.0426,
found (MꢀH) = 268.0427.
8. Y. Liu, Y. Zhang, C. Hu, J.ꢀP. Wan, C. Wen, RSC Adv.
2014, 4, 35528.
9. (a) Z. Wu, H. Song, X. Cui, C. Pi, W. Du, Y. Wu, Org. Lett.
2013, 15, 1270; (b) Q. Wu, D. Zhao, X. Qin, J. Lan, J. You,
Chem. Commun. 2011, 47, 9188; (c) J. Bai, X. Cui, H. Wang, Y.
Wu, Chem. Commun. 2014, 50, 8860.
3-((1-methyl-1H-indol-3-yl)thio)benzoic acid (5e): White solid,
m.p. 142ꢀ146 ℃; Yield ꢀ 238 mg (84%); 1H-NMR (300 MHz,
CDCl3+DMSO): δ 7.84 – 7.59 (m, 2H), 7.56 – 7.38 (m, 3H), 7.33 –
7.08 (m, 4H), 3.88 (s, 3H); 13C-NMR (75 MHz, CDCl3+DMSO): δ
167.2, 139.5, 136.9, 134.7, 130.8, 129.1, 128.8, 127.9, 126.2, 125.4,
121.9,119.8, 118.5, 109.3, 98.8, 32.5; IR (neat, cmꢀ1): 3305, 2972,
2845, 1892, 1745, 1490, 1453, 1413, 1294, 1076, 773; ESI-MS
(m/z): Calculated for C16 H13 O2 N S = 283, found (MꢀH) = 282.
10. M. Chen, Z.ꢀT. Huang, Q.ꢀY. Zheng, Chem. Commun. 2012, 48
,
11686.
11. The trivalent phosphorous compound as oxidizing agent leads
to triphenylphosphine oxide or the corresponding phosphinic
acid as a byꢀproduct (see ref.4, 9a and 9c).
12. G. Kumaraswamy, R. Raju, Adv. Synth. Catal. 2014, 356, 2591.
13. In this case, we have isolated 4ꢀMePhꢀSO2ꢀSꢀPhꢀ4Me as by
product (~ 20%).
Notes and references:
a Organic & Biomolecular Chemistry Division,
CSIRꢀIndian Institute of Chemical Technology, Hyderabadꢀ500 607,
India.
14. At this juncture, we cannot exclude the formation of putative
†Fax:
+
91ꢀ40ꢀ27193275; Tel:
+
91ꢀ40ꢀ27191614; †Eꢀmail:
intermediate [A] via thermal decomposition of iodine in the
gkswamy_iict@yahoo.co.in
b Academy of Scientific and Innovative Research.
presence of indole to form iodine radicals which then abstracts
chlorine atom to give iodochlorine and sulfonyl radical which
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13
NMR spectras available free of charge via Internet]. See
DOI: 10.1039/b000000x/
C
then couples to give putative intermediate [A] as shown below.
See ref. (a) J. Gromada, K. Matyjaszewski, Macromolecules
2001, 34, 7664; (b) X. Gao, X. Pan, J. Gao, H. Huang, G. Yuan,
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Carethers, J. A. Kennedy, D. Thueson, J. C. Chestnut, R. L.
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(b) A. Y. Sizov, A. N. Kovergin, A. F. Ermolov, Russ. Chem.
Rev. 2003, 72, 357.
heat
I2
2I
1,4ꢀdioxane
O
O
2I
O
O
I
S
S
A
Ph
Cl
Ph
_
ICl
2a
3. (a) X. –L. Fang, R. –Y. Tang, P. Zhong, J. –H. Li, Synthesis
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C. C. Browder, M. O. Mitchell, R. L. Smith, G. elꢀStdayman
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6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012