A Sulfonylation Reaction: Direct Synthesis of 2-Sulfonylindoles from Sulfonyl Hydrazides and Indoles

Article abstract of DOI:10.1055/s-0036-1588398

A metal-free synthesis of 2-sulfonylindole derivatives has been developed through a novel TBHP/I₂-mediated coupling of C3/unsubstituted indoles with sulfonyl hydrazides. The reaction utilizes readily available starting materials under mild reaction conditions, providing an alternative and attractive approach to 2-sulfonylindoles with high yields. The developed synthetic procedure is suitable for both N-protected or unprotected indoles.

Full text of DOI:10.1055/s-0036-1588398

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–G
letter
A
R. Rahaman, P. Barman
Letter
Synlett
A Sulfonylation Reaction: Direct Synthesis of 2-Sulfonylindoles
from Sulfonyl Hydrazides and Indoles
Rajjakfur Rahaman
R2
Pranjit Barman*
N
R1
O
S
I2 (20 mol%)
R3
R2
+
Department of Chemistry, National Institute of Technology
Silchar, Silchar-788010, India
barmanpranjit@yahoo.co.in
O
S
N
R1
TBHP (2 equiv)
DCE, r.t., 2 h
O
R3
NHNH2
O
Metal-free
Mild conditions
Short reaction time
Broad substrate scope
Gram scale
18 examples
up to 96% yield
R1 = H, Me
R2 = H, Br, OMe, Cl, Br, F
R3 = aryl, alkyl, naphthyl
Received: 13.10.2016
Accepted after revision: 29.12.2016
Published online: 24.01.2017
SO2Ph
CONH2
Cl
DOI: 10.1055/s-0036-1588398; Art ID: st-2016-b0687-l
N
H
O
S
Abstract A metal-free synthesis of 2-sulfonylindole derivatives has
been developed through a novel TBHP/I2-mediated coupling of C3/un-
substituted indoles with sulfonyl hydrazides. The reaction utilizes readi-
ly available starting materials under mild reaction conditions, providing
an alternative and attractive approach to 2-sulfonylindoles with high
yields. The developed synthetic procedure is suitable for both N-pro-
tected or unprotected indoles.
L-737, 126
(anti HIV-1 RT)
N
O
NHSO2CF3
NMe2
O
S
SO2NHMe
O
F
bis-sulfone derivative
(cannabinoid CB2 receptor ligands)
N
H
sumatriptan
(anti-migraine)
Key words direct synthesis, sulfonylation, 2-sulfonylindoles, sulfonyl
hydrazides, indoles
i-Pr
O
S
O
(CH2)3
N
(CH2)2
OMe
OMe
Organosulfones are important intermediates for phar-
maceuticals, agrochemicals, and activating and protecting
groups.1 Indoles represents a prominent structural motif
found in naturally occurring compounds and pharmaceuti-
cally important agents (Figure 1).2,3 It has been widely prov-
en that the C2 position of the indole has less priority com-
pared to the C3 position. Hence, the direct C2 functionaliza-
tion of indole has been more challenging and less studied.
Sulfur-containing group when present in a molecular
structure either as a sulfanyl, a sulfenyl, or a sulfonyl, it
adds variety to the chemical architecture and also enhances
biological activity of the compound.4
Particularly, 2-sulfonylindoles affects the inhibition of
nucleoside triphosphate hydrolase enzyme, and the sulfo-
nyl group of the 2-sulfonylindoles acts as a temporary func-
tional group which can be removed later by β-elimination.5
Generally, indolyl aryl sulfones are synthesized via the
oxidation of the corresponding arylthioindoles.6 During the
past few years, alternative methodologies have been devel-
oped for the synthesis of 3-arylsulfonyl indoles using aryl
N
O
Me
SR 33805
(Ca2+ channel antagonist)
Me
Figure 1 Some biologically active indolyl aryl sulfones
sulfinic acids or aryl sulfonyl halides as sulfonylation re-
agents.7 Meanwhile, only a few methods have been devel-
oped for 2-arylsulfonyl indoles.8 However, still the reported
methods have some drawbacks such as using nonstable,
hazardous, and mutagenic starting materials, difficulty in
handling and storage, and the requirements of harsh reac-
tion conditions and prolonged reaction time. Therefore, it is
highly desirable to develop an alternative and facile catalyt-
ic methodology to construct 2-sulfonylindoles from a syn-
thetic viewpoint.
Due to their ease of handling, high efficiency, commer-
cial availability, low toxicity, mild reaction conditions, and
metal-free features, molecular iodine and its salts have
emerged as a promising alternative to catalyse oxidative
sulfonylation recently.9 Numerous methods have demon-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

B
R. Rahaman, P. Barman
Letter
Synlett
strated impressive advancements of iodine-catalyzed sulfo-
nylation of heteroaromatic compounds and C–C unsaturat-
ed bonds.10
tries 13–16). Moreover, there was no product formation ob-
served in the absence of I2 (Table 1, entry 27), and only a
trace amount of the product was obtained without using
TBHP in the reaction (Table 1, entry 28).
In recent years, arylsulfonyl hydrazides have emerged as
excellent synthons for many organic transformations.11 De-
pending upon the conditions of reaction they can act as a
sulfur electrophiles or nucleophiles.12,9f Compared to the
other sulfonylating agents sulfonyl hydrazides are much
more amenable to handling, because they are readily acces-
sible solids, not sensitive to air and moisture, free of un-
pleasant odor, exhibit high reactivity, react under relatively
mild conditions, and are eco-friendly byproducts (water
and N2). However, to the best of our knowledge, the forma-
tion of 2-sulfonylindoles from sulfonyl hydrazides and in-
doles has not been explored. In our effort to benign proto-
cols, we have continuously tried to endorse the use of non-
toxic medium. Therefore, in our approach, we concentrated
on the potent combination of a nontoxic medium and tran-
sition-metal-free conditions with disulfide or sulfonyl hy-
drazide species.13 Herein, we developed an iodine-catalyzed
sulfonylation of indoles with sulfonyl hydrazides using DCE
as solvent, affording 2-arylsulfonyl indoles in good to excel-
lent yields (Scheme 1).
Table 1 Optimization of the Reaction Conditionsa
O
S
O
S
catalyst
oxidant
NHNH2
+
N
N
O
O
H
H
1a
2a
3a
Entry
Catalyst
(mol%)
2a
(equiv)
Solvent
Oxidant
(equiv)
Yield
(%)b
1
2
NIS (10)
KI (10)
NH4I (10)
TBAI (10)
I2 (10)
I2 (20)
I2 (30)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
–
1
1
1
1
1
1
1
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
DCE
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1.5)
TBHP (2)
TBHP (3)
H2O2 (2)
DTBP (2)
K2S2O8 (2)
Air (O2)
40
30
37
32
50
70
70
85
85
90
92
92
60
70
65
15
82
42
35
40
DCE
3
DCE
4
DCE
5
DCE
6
DCE
7
DCE
8
DCE
9
DCE
O
S
O
S
I2 (20 mol%)
R2
R3
R3
NHNH2
R2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
DCE
+
TBHP (2 equiv)
DCE, r.t., 2 h
N
R1
N
R1
O
O
DCE
DCE
Scheme 1 Some biologically active indolyl aryl sulfones
DCE
DCE
In order to achieve optimum reaction conditions, indole
(1a) and benzenesulfonyl hydrazide (2a) were chosen as
the model substrates. To our delight, the desired product 2-
benzenesulfonylindole (3a) was obtained in 50% yield when
the reaction was carried out by using I2 (10 mol%) and TBHP
(1 equiv, 70% in water) in 1,2-dichloroethane (DCE) for two
hours in an open atmosphere at room temperature (Table 1,
entry 5). An increase to 20 mol% of I2 brought about a rea-
sonable rise in the yield to 70% (Table 1, entry 6). However,
further increase in the I2 concentration did not enhance the
yield of the desired product (Table 1, entry 7). Higher yield
was observed when 2a was employed in excess amount (Ta-
ble 1, entry 8). As illustrated in entries 1–4, different types
of iodine-containing catalysts including NIS, KI, NH4I, and
TBAI were examined in the model reaction, and we found
that these catalysts hardly facilitate the reaction. Thereaf-
ter, we screened the effect of various solvents on the reac-
tion and DCE found to be particularly effective for this
transformation. To increase the TBHP loading of 1.5 equiva-
lents improved the yield remarkably, and two equivalents
of TBHP were found to be sufficient for a reasonably im-
proved yield of the product (Table 1, entries 10 and 11).
Screening a range of oxidants such as H2O2, di-tert-butyl
peroxide (DTBP), K2S2O8, and O2 revealed that other oxi-
dants were ineffective for this transformation (Table 1, en-
DCE
DCE
CH2Cl2
toluene
MeCN
MeOH
H2O
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
–
trace
DMSO
DMF
THF
trace
trace
45
1.4-dioxane
EtOAc
DCE
40
30
c
–
I2 (20)
DCE
trace
a Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst (0.1 mmol, 20
mol%), oxidant (1 mmol), solvent (2 mL), r.t., 2 h under air; NIS = N-iodo-
succinimide; TBHP = tert-butyl hydroperoxide; TBAI = tetrabutylammonium
iodide; DTBP = di-tert-butyl peroxide.
b Isolated yields after column chromatography based on 1a.
c 3a was not observed (TLC analysis).
After all, the use of I2 and TBHP were crucial for this re-
action, and the optimum reaction conditions for the C2-sul-
fonylation of indoles were chosen as follows: 1a (1 equiv),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

C
R. Rahaman, P. Barman
Letter
Synlett
2a (2 equiv), I2 (20 mol%), TBHP (2 equiv) in DCE at room
temperature for two hours (Table 1, entry 11). With the op-
timized reaction conditions in hand, we next explored the
substrate scope and limitations of this new method.
moderate to excellent yields. The electronic effect of the
substituents on the indole moiety was also investigated
(Scheme 3). Indoles bearing electron-donating groups such
as 5-MeO, 4-Me, and 7-Me gave better reactivity and deliv-
er high product yields. Substrate such as 5-O2N indole did
not give the corresponding sulfenylated product.
Under the optimized conditions, a range of substituted
aryl sulfonyl hydrazides were introduced to react with in-
dole (1a) to give 2-arylsulfonyl indoles in good to excellent
yields (Scheme 2, 3a–g). Various functional groups such as
halogen, methoxy, and methyl could smoothly react with
1a under the optimized reaction conditions. However, it
was observed that sulfonyl hydrazides bearing electron-
withdrawing groups deliver the product with high yield. It
should be noted that cleavage of the C–halogen bond was
not observed. Naphthylsulfonyl hydrazide also reacted with
1a to give the desired product with high yield without any
difficulties (Scheme 2, 3h). To our delight, besides aromatic
sulfonyl hydrazides, aliphatic sulfonyl hydrazides were also
suitable for this transformation, generating the correspond-
ing products 3i in excellent yields.
R2
N
R1
O
S
1
I2 (20 mol%)
R2
+
TBHP (2 equiv)
DCE, 2 h, r.t.
N
R1
O
S
O
NHNH2
3
O
2a
Cl
O
S
O
S
N
N
O
O
H
Me
3j (75%)
3k (75%)
To further extend the applications of the reaction pre-
sented here the substrate scope of indoles was investigated
under standard conditions. All reactions were performed
well and afforded the corresponding 2-sulfonyl indoles in
Br
O
MeO
O
S
S
N
O
N
O
H
H
3l (65%)
3m (96%)
O
S
O
S
O
O
S
I2 (20 mol%)
R3
R3
NHNH2
+
S
TBHP (2 equiv)
DCE, r.t., 2 h
N
N
O
O
N
N
Cl
O
O
H
H
H
H
1a
2
3
3o (80%)
3n (92%)
O
S
O
S
O
S
O
S
N
N
O
O
H
H
N
O
N
O
3a (92%)
3b (90%)
H
H
3p (96%)
3q (89%)
O
S
O
S
Br
O
Cl
Br
S
Cl
N
N
O
O
N
O
H
H
H
3c ( 88%)
3d (85%)
3r (69%)
Scheme 3 Substrate scope of various indoles with 2a. Reagents and
conditions: 1 (0.5 mmol), 2a (1.0 mmol), I2 (0.1 mmol, 20 mol%), TBHP
(1.0 mmol), DCE (2 mL), r.t., 2 h; isolated yield.
O
S
O
S
OMe
F
N
N
O
O
H
H
3e (89%)
3f (82%)
To gather more information, several control experi-
ments were performed to gain an insight into the reaction
mechanism (Scheme 4). A reaction of indole 1a and sulfonyl
hydrazides 2b in the presence of a radical scavenger under
the standard conditions resulted in a decrease in product
yield. The desired product 2-sulfonylindole 3b was ob-
tained in 40%, 10%, and 0% yield in the presence of 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO), 2,6-di-tert-butyl-
4-methylphenol (BHT), and hydroquinone, respectively
(Scheme 4). The reaction was suppressed by a radical scav-
enger and implies that the reaction pathway is likely to in-
volve a radical process. In the absence of indole 1a, the sul-
fonyl hydrazide 2b decompose to form benzenesulfonothio-
O
S
O
S
CF3
N
N
O
O
H
H
3h (90%)
3g (79%)
O
S
Me
N
O
H
3i (92%)
Scheme 2 Sulfonylation of indole (1a) with sulfonyl hydrazides. Reagents
and conditions: 1a (0.5 mmol), 2 (1.0 mmol), I2 (0.1 mmol, 20 mol%), TBHP
(1.0 mmol), DCE (2 mL), r.t., 2 h; isolated yield based on 1a.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

D
R. Rahaman, P. Barman
Letter
Synlett
ate (3aa, 70%) along with
a small amount of 1,2-
Possible radicals:
diphenyldisulfane (3ab, 15%). Under the optimized condi-
tions 3ab converted into 3aa. The intermediate 3aa was
confirmed by the treatment of 1a with 3aa, which provided
the desired product 3b in 80% yield (Scheme 5). Since trace
amount of product was obtained when the reaction per-
formed without using TBHB (Table 1, entry 28), indicates
that I2 does not react directly with the substrates. Iodine is
likely converted into another intermediate in the presence
of TBHP prior to reacting with sulfonyl hydrazide or indole.
R: I•, t-BuO•, t-BuOO•, HO•
Sulfonylation of indoles:
R•
R•
R
H
R H
O
O
S
O
R3
S
NHNH2
R3
NNH2
R3
S
N NH
O
O
A
O
B
2
O
S
R•
R2
R3
R
N
R1
O
H
3
R
H
R2
R•
R2
N
N
O
S
R1
O
O
1
R3
H
+ N2
1a
+
standard conditions
R3
S
S
N
R1
O
S
O
radical inhibitors
(1 equiv)
N
O
C
O
NHNH2
D
H
3b
O
2b
TEMPO
BHT
hydroquinone
40%
10%
0%
Scheme 5 Plausible reaction mechanism
tween I2 and TBHP. The resulting sulfonyl radical could sub-
sequently undergo addition to indole 1, followed by iodine-
catalyzed sulfonylation which afforded 2-sulfonylindole 3.
To showcase the practicability of the developed method,
the reaction of indole 1a and sulfonyl hydrazide 2a was
scaled up to 10 mmol, and the desired product 3a was ob-
tained without any significant loss in yield (1.3 g, 85%,
Scheme 6).
O
S
S
standard
conditions
O
O
S
3aa, 70%
NHNH2
+
O
S
S
2b
3ab, 15%
standard
conditions
O
S
S
S
S
O
S
O
S
I2 (20 mol%)
O
NHNH2
+
3ab
3aa, 85%
TBHP (2 equiv)
DCE, r.t., 2 h
N
N
O
O
H
H
1a
2a
3a, 1.3 g, 85%
Scheme 6 Gram-scale reaction
N
standard
conditions
O
S
H
1a
+
In conclusion, we have successfully disclosed a facile
and efficient method for the synthesis of 2-sulfonylindoles
N
O
S
O
H
S
in
a highly functional-group compatible manner via
3b, 80%
O
I2/TBHP-mediated reaction of indoles with commercially
available sulfonyl hydrazide. The novel method refrains
from using expensive metal catalysts and operates effi-
ciently under an open atmosphere at room temperature.
The unique method holds significant potential for applica-
tion to a series of new organic reactions. The synthetic
method presented here has many advantages, such as sim-
ple operation, short reaction time, inexpensive I2 catalyst,
broad scope of substrate, and excellent yields, and promises
to be a greener alternative to earlier methods. Further ef-
forts in this area are in progress in our laboratory.
3aa
Scheme 4 Control experiments
Based on the aforementioned results, existing litera-
ture,14 and the control experiments a possible mechanism
is outlined in Scheme 5. Since the reactions were extremely
inactive or did not occur if neither I2 nor TBHP was em-
ployed under the optimized reaction conditions (Table 1,
entries 27 and 28), this implies that to lead to the desired 2-
sulfonylindoles both I2 and TBHP did not directly react with
the starting materials during the reaction. The transforma-
tion is presumed to involve a sulfonyl radical C, which is
formed by the sequential N–H abstraction by the radicals
(I•, t-BuO•, t-BuOO•, or HO•) generated by the reaction be-
Acknowledgment
The authors are thankful to the Director, NIT Silchar for financial sup-
port. MHRD, Govt. of India is acknowledged for the doctorate fellow-
ship (MHRD GATE fellowship) received by R.F.R. The authors are also
thankful to CSIR-NEIST Jorhat and IIT Guwahati for spectral analysis.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

E
R. Rahaman, P. Barman
Letter
Synlett
Supporting Information
J. Org. Chem. 2014, 79, 1778. (c) Karchava, A. V.; Shuleva, I. S.;
Ovcharenko, A. A.; Yurovskaya, M. A. Chem. Heterocycl. Compd.
2010, 46, 291; Khim. Geterotsikl. Soedin. 2010, 373. (d) Wenkert,
E.; Moeller, P. D. R.; Piettre, S. R.; McPhail, A. T. J. Org. Chem.
1987, 52, 3404. (e) Yang, Y.; Li, W.; Xia, C.; Ying, B.; Shen, C.;
Zhang, P. ChemCatChem 2016, 8, 304.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588398.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(9) (a) Zhang, J.; Shao, Y.; Wang, H.; Luo, Q.; Chen, J.; Xu, D.; Wan, X.
Org. Lett. 2014, 16, 3312. (b) Tang, S.; Wu, Y.; Liao, W.; Bai, R.;
Liu, C.; Lei, A. Chem. Commun. 2014, 50, 4496. (c) Li, X.; Xu, X.;
Tang, Y. Org. Biomol. Chem. 2013, 11, 1739. (d) Li, X.; Xu, X.;
Zhou, C. Chem. Commun. 2012, 48, 12240. (e) Li, X.; Xu, X.; Hu,
P.; Xiao, X.; Zhou, C. J. Org. Chem. 2013, 78, 7343. (f) Li, X.; Xu,
X.; Shi, X. Tetrahedron Lett. 2013, 54, 3071. (g) Yang, F.-L.; Tian,
S.-K. Angew. Chem. Int. Ed. 2013, 52, 4929.
(10) (a) Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 45, 979.
(b) Froehr, T.; Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.;
Nachtsheim, B. J. Org. Lett. 2011, 13, 3754. (c) Lamani, M.;
Prabhu, K. R. J. Org. Chem. 2011, 76, 7938. (d) Tian, J.-S.; Ng, K.
W. J.; Wong, J.-R.; Loh, T.-P. Angew. Chem. Int. Ed. 2012, 51, 9105.
(e) Nobuta, T.; Tada, N.; Fujiya, A.; Kariya, A.; Miura, T.; Itoh, A.
Org. Lett. 2013, 15, 574. (f) Lv, Y.; Li, Y.; Xiong, T.; Lu, Y.; Liu, Q.;
Zhang, Q. Chem. Commun. 2014, 50, 2367. (g) Wang, G.; Yu, Q.-
Y.; Chen, S.-Y.; Yu, X.-Q. Org. Biomol. Chem. 2014, 12, 414.
(h) Wu, X.-F.; Gong, J.-L.; Qi, X. Org. Biomol. Chem. 2014, 12,
5807. (i) Jiang, Q.; Xu, B.; Zhao, A.; Jia, J.; Liu, T.; Guo, C. J. Org.
Chem. 2014, 79, 8750. (j) Zhao, D.; Shen, Q.; Li, J.-X. Adv. Synth.
Catal. 2015, 357, 339. (k) Tang, S.; Liu, K.; Long, Y.; Gao, X.; Gao,
M.; Lei, A. Org. Lett. 2015, 17, 2404.
(11) (a) Qiu, J.-K.; Hao, W.-J.; Wang, D.-C.; Wei, P.; Sun, J.; Jiang, B.;
Tu, S.-J. Chem. Commun. 2014, 50, 14782. (b) Zhang, J.; Shao, Y.;
Wang, H.; Luo, Q.; Chen, J.; Xu, D.; Wan, X. Org. Lett. 2014, 16,
3312. (c) Majumdar, P.; Pati, A.; Patra, M.; Behera, R. K.; Behera,
A. K. Adv. Synth. Catal. 2014, 114, 2942. (d) Kang, X.; Yan, R.; Yu,
G.; Pang, X.; Liu, X.; Li, X.; Xiang, L.; Huang, G. J. Org. Chem. 2014,
79, 10605. (e) Guo, S.-R.; He, W.-M.; Xiang, J.-N.; Yuan, Y.-Q.
Chem. Commun. 2014, 50, 8578. (f) Zhao, X.; Zhang, L.; Li, T.; Liu,
G.; Wang, H.; Lu, K. Chem. Commun. 2014, 50, 13121. (g) Tang,
S.; Wu, Y.; Liao, W.; Bai, R.; Liu, C.; Lei, A. Chem. Commun. 2014,
50, 4496.
(12) (a) Singh, R.; Raghuvanshi, D. S.; Singh, K. N. Org. Lett. 2013, 15,
4202. (b) Singh, N.; Singh, R.; Raghuvanshi, D. S.; Singh, K. N.
Org. Lett. 2013, 15, 5874. (c) Singh, R.; Allam, B. K.; Singh, N.;
Kumari, K.; Singh, S. K.; Singh, K. N. Adv. Synth. Catal. 2015, 357,
1181.
(1) (a) The Chemistry of Sulfones and Sulfoxides; Patai, S.;
Rappoport, Z.; Stirling, C. J. M., Eds.; Wiley: New York, 1988.
(b) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon
Press: Oxford, 1993.
(2) (a) Ban, Y.; Murakami, Y.; Iwasawa, Y.; Tsuchiya, M.; Takano, N.
Med. Res. Rev. 1988, 8, 231. (b) Seigler, D. S. Plant Secondary
Metabolism; Springer: New York, 2001, 628–667. (c) Katritzky,
A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry; Per-
gamon Press: Oxford, 2000. (d) Hibino, S.; Choshi, T. Nat. Prod.
Rep. 2002, 19, 148. (e) Kochanowska-Karamyan, A. J.; Hamann,
M. T. Chem. Rev. 2010, 110, 4489. (f) Humphrey, G. R.; Tsutumi, J.
T. Chem. Rev. 2006, 106, 2875. (g) Takayama, H.; Tsutsumi, S. I.;
Kitajima, M.; Santiarworn, D.; Liawruangrath, B.; Aimi, N. Chem.
Pharm. Bull. 2003, 51, 232.
(3) (a) Campbell, J. A.; Bordunov, V.; Borka, C. A.; Browner, M. F.;
Kress, J. M.; Mirzadegan, T.; Ramesha, C.; Sanpablo, B. F.; Stabler,
R.; Takahara, P.; Villasenor, A.; Walker, K. A. M.; Wang, J.-H.;
Welch, M.; Weller, P. Bioorg. Med. Chem. Lett. 2004, 14, 4741.
(b) Holenz, J.; Pauwels, P. J.; Diaz, J. L.; Mercèr, R.; Codony, X.;
Buschmann, H. Drug Discovery Today 2006, 11, 283. (c) Bentley,
J. M.; Bickerdike, M. J.; Hebeisen, P.; Kennett, G. A.; Lightowler,
S.; Mattei, P.; Mizrahi, J.; Morley, T. J.; Plancher, J.-M.; Richter,
H.; Roever, S.; Taylor, S.; Vickers, S. P. WO 2002051844A1, Chem.
Abstr. 2002, 137, 78856. (d) Williams, T. M.; Ciccarone, T. M.;
MacTough, S. C.; Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini,
E. A.; 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. (e) Tong, L.; Shankar, B. B.; Chen,
L.; Rizvi, R.; Kelly, J.; Gilbert, E.; Huang, C.; Yang, D.-Y.;
Kozlowski, J. A.; Shih, N.-Y.; Gonsiorek, W.; Hipkin, R. W.;
Malikzay, A.; Lunn, C. A.; Lundell, D. J. Bioorg. Med. Chem. Lett.
2010, 20, 6785. (f) Romey, G.; Lazdunski, M. J. Pharmacol. Exp.
Ther. 1994, 271, 1348.
(4) (a) Trost, B. M. In Comprehensive Organic Chemistry; Pergamon
Press: Oxford, 1991. (b) Simpkins, N. S. In Sulfones in Organic
Synthesis; Baldwin, J. E., Ed.; Pergamon Press: Oxford, 1993.
(5) (a) Caddick, S.; Aboutayab, K.; West, R. Synlett 1993, 231.
(b) Asai, T.; Takeuchi, T.; Diffenderfer, J.; Sibley, D. L. Antimicrob.
Agents Chemother. 2002, 46, 2393.
(6) (a) Bernotas, R.; Antane, S.; Harrison, B.; Lenicek, S.; Coupet, J.;
Schechter, L.; Smith, D.; Zhang, G. M. Bioorg. Med. Chem. Lett.
2004, 14, 5499. (b) Broggini, G.; Diliddo, D.; Zecchi, G. J. Hetero-
cycl. Chem. 1991, 28, 89. (c) Vedejs, E.; Little, J. D. J. Org. Chem.
2004, 69, 1794. (d) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S.
A.; Liu, X. Chem. Soc. Rev. 2015, 44, 291. (e) Lee, C.-F.; Liu, Y.-C.;
Badsara, S. S. Chem. Asian J. 2014, 9, 706.
(13) (a) Rahaman, R.; Devi, N.; Barman, P. Tetrahedron Lett. 2015, 56,
4224. (b) Rahaman, R.; Devi, N.; Bhagawati, J. R.; Barman, P. RSC
Adv. 2016, 6, 18929. (c) Rahaman, R.; Devi, N.; Sarma, K.;
Barman, P. RSC Adv. 2016, 6, 10873. (d) Devi, N.; Rahaman, R.;
Barman, P. Eur. J. Org. Chem. 2016, 384.
(14) (a) Singh, R.; Allam, B. K.; Singh, N.; Kumari, K.; Singh, S. K.;
Singh, K. N. Org. Lett. 2015, 17, 2656. (b) Yotphan, S.; Sumunnee,
L.; Beukeaw, D.; Buathongjan, C.; Reutrakul, V. Org. Biomol.
Chem. 2016, 14, 590. (c) Qian, H.; Huang, X. Tetrahedron Lett.
2002, 43, 1059. (d) Wei, W.; Wen, J.; Yang, D.; Jing, H.; You, J.;
Wang, H. RSC Adv. 2015, 5, 4416. (e) Abe, H.; Suzuki, H. Bull.
Chem. Soc. Jpn. 1999, 72, 787. (f) Nair, V.; Augustine, A.; Suja, T.
D. Synthesis 2002, 2259. (g) Meesin, J.; Katrun, P.;
Pareseecharoen, C.; Pohmakotr, M.; Reutrakul, V.; Soorukram,
D.; Kuhakarn, C. J. Org. Chem. 2016, 81, 2744. (h) Senadi, G. C.;
Guo, B.-C.; Hub, W.-P.; Wang, J.-J. Chem. Commun. 2016, 52,
11410. (i) Yang, F.-L.; Wang, F.-X.; Wang, T.-T.; Wanga, Y.-J.; Tian,
S.-K. Chem. Commun. 2014, 50, 2111. (j) Wen, J.; Wei, W.; Xue,
S.; Yang, D.; Lou, Y.; Gao, C.; Wang, H. J. Org. Chem. 2015, 80,
(7) (a) Boroujeni, K. P. J. Sulfur Chem. 2010, 31, 197. (b) Samant, S.
D.; Singh, D. U.; Singh, P. R. Tetrahedron Lett. 2004, 45, 9079.
(c) Yadav, J. S.; Reddy, B. V. S.; Krishna, A. D.; Swamy, T. Tetrahe-
dron Lett. 2003, 44, 6055. (d) Gao, D.; Parvez, M.; Back, T. G.
Chem. Eur. J. 2010, 16, 14281. (e) Boroujeni, K. P. Bull. Korean
Chem. Soc. 2010, 31, 1887.
(8) (a) Xiao, F.; Chen, H.; Xie, H.; Chen, S.; Yang, L.; Deng, G.-J. Org.
Lett. 2014, 16, 50. (b) Katrun, P.; Mueangkaew, C.; Pohmakotr,
M.; Reutrakul, V.; Jaipetch, T.; Soorukram, D.; Kuhakarn, C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

F
R. Rahaman, P. Barman
Letter
Synlett
4966. (k) Su, Y.; Zhou, X.; He, C.; Zhang, W.; Ling, X.; Xiao, X.
J. Org. Chem. 2016, 81, 4981. (l) Yang, Z.; Hao, W.-J.; Wang, S.-L.;
Zhang, J.-P.; Jiang, B.; Li, G.; Tu, S.-J. J. Org. Chem. 2015, 80, 9224.
(15) General Procedure for the Synthesis of 2-Sulfonylindoles
To a mixture of indole 1 (0.5 mmol) with sulfonyl hydrazide 2 (1
mmol), iodine (20 mol%), TBHP (70% in water, 1 mmol) in DCE
(2 mL). The resulting reaction mixture was stirred at r.t. for 2 h.
Upon completion, distilled deionized H2O (10 mL) and sat.
Na2S2O3 (10 mL) were added, and the mixture was extracted
with EtOAc (3 × 20 mL). The combined organic layer was
washed with sat. brine (20 mL), dried over anhydrous Na2SO4,
and concentrated in vacuum. The crude product was purified by
column chromatography using EtOAc–hexanes (1:5) as eluent to
afford the desired 2-sulfonylindole 3.
2-[(4-Fluorophenyl)sulfonyl]-1H-indole (3f)8a
White solid (112.9 mg, 82% yield); mp 155–157 °C. 1H NMR (500
MHz, CDCl3): δ = 8.95 (br s, 1 H), 8.03 (d, J = 8.5 Hz, 2 H), 7.57–
7.52 (m, 3 H), 7.36 (t, J = 7.0 Hz, 1 H), 7.24 (t, J = 7.5 Hz, 1 H),
7.16 (d, J = 9 Hz, 2 H). 13C NMR (125 MHz, CDCl3): δ = 166 (d, J =
251.6 Hz), 136.4 (d, J = 3 Hz), 135, 130 (d, J = 9.6 Hz), 128.3,
124.9, 123.4, 121.3, 119.1, 116.3 (d, J = 22.6 Hz), 111.8, 109.
Anal. Calcd (%) for C14H10FNO2S: C, 61.08; H, 3.66; N, 5.09.
Found: C, 61.05; H, 3.67; N, 5.06.
2-(Naphthalen-2-ylsulfonyl)-1H-indole (3h)8a
White solid (138.3 mg 90% yield); mp 156–158 °C. 1H NMR (500
MHz, CDCl3): δ = 9.05 (br s, 1 H), 8.46 (s, 1 H), 7.96–7.93 (m, 2
H), 7.72 (d, J = 8.0 Hz, 1 H), 7.65–7.61 (m, 2 H), 7.48–7.45 (m, 2
H), 7.38–7.33 (m, 2 H), 7.29–7.25 (m, 2 H), 7.16–7.13 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 138.5, 136.4, 133.6, 131.2, 130.5,
128.9, 128.1, 127.5, 126.8, 126.2, 124.9, 124.6, 123.3, 122.9,
120.8, 119.5, 111.4, 108.6. Anal. Calcd (%) for C18H13NO2S: C,
70.34; H, 4.26; N, 4.56. Found: C, 70.31; H, 4.23; N, 4.57.
2-(Methylsulfonyl)-1H-indole (3i)8a
(16) See Supporting Information for detailed experimental proce-
dures and characterization data.
2-(Phenylsulfonyl)-1H-indole (3a)8a
White solid (118.4 mg, 92% yield); mp 159–161 °C. 1H NMR (500
MHz, CDCl3): δ = 8.81 (br s, 1 H), 8.04 (d, J = 7.0 Hz, 2 H), 7.66 (d,
J = 9.0 Hz, 1 H), 7.50 (d, J = 2.5 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H),
7.31 (d, J = 6.0 Hz, 1 H), 7.21–7.17 (m, 3 H), 7.14 (t, J = 7.0 Hz, 1
H). 13C NMR (125 MHz, CDCl3): δ = 141, 136.3, 133.5, 130.5,
128.9, 128.5, 124.6, 122.9, 120.7, 119.5, 111.4, 108.9. Anal.
Calcd (%) for C14H11NO2S: C, 65.35; H, 4.31; N, 5.44. Found: C,
65.37; H, 4.32; N, 5.45.
White solid (89.8 mg, 92% yield); mp 184–186 °C. 1H NMR (500
MHz, CDCl3): δ = 9.01 (br s, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.43 (d,
J = 8.0 Hz, 1 H), 7.29–7.25 (m, 1 H), 7.22–7.16 (m, 2 H), 3.25 (s, 3
H). 13C NMR (125 MHz, CDCl3): δ = 136.4, 133.3, 126.9, 126.2,
122.9, 121, 111.6, 108.2, 45.2. Anal. Calcd (%) for C9H9NO2S: C,
55.37; H, 4.65; N, 7.17. Found: C, 55.40; H, 4.63; N, 7.15.
5-Methoxy-2-(phenylsulfonyl)-1H-indole (3m)8a
2-Tosyl-1H-indole (3b)8a
White solid (122.1 mg, 90% yield); mp 195–197 °C. 1H NMR (500
MHz, CDCl3): δ = 9.02 (br s, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 7.65 (d,
J = 7.5 Hz, 1 H), 7.50 (d, J = 2.5 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H),
7.30–7.27 (m, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2
H), 2.33 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 143.7, 136.3,
135.3, 130.2, 139.3, 128.9, 126.1, 122.8, 120.7, 119.5, 111.3,
108.5, 20.7. Anal. Calcd (%) for C15H13NO2S: C, 66.40; H, 4.83; N,
5.16. Found: C, 66.43; H, 4.81; N, 5.15.
White solid (137.9 mg, 96% yield); mp 135–137 °C. 1H NMR (400
MHz, CDCl3): δ = 9.01 (br s, 1 H), 8.02 (d, J = 8.0 Hz, 2 H), 7.57–
7.51 (m, 3 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.22 (s, 1 H), 7.16–7.12 (m,
2 H), 3.81 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 155, 140.9,
134.1, 133.5, 132.6, 129.8, 128.1, 127.7, 117.6, 112.3, 109, 102.3,
55.5. Anal. Calcd (%) for C15H13NO3S: C, 62.70; H, 4.56; N, 4.87.
Found: C, 62.67; H, 4.57; N, 4.85.
4-Methyl-2-(phenylsulfonyl)-1H-indole (3n)8a
2-[(4-Chlorophenyl)sulfonyl]-1H-indole (3c)8a
White solid (124.8 mg, 92% yield); mp 166–169 °C. 1H NMR (400
MHz, CDCl3): δ = 9.01 (br s, 1 H), 7.96 (d, J = 8.4 Hz, 2 H), 7.50–
7.45 (m, 3 H), 7.32–7.27 (m, 3 H), 6.96 (d, J = 7.2 Hz, 1 H), 2.51 (s,
3 H). Anal. Calcd (%) for C15H13NO2S: C, 66.40; H, 4.83; N, 5.16.
Found: C, 66.38; H, 4.80; N, 5.17.
White solid (128.4 mg, 88% yield); mp 146–148 °C. 1H NMR (500
MHz, CDCl3): δ = 8.82 (br s, 1 H), 7.83 (d, J = 9 Hz, 2 H), 7.75 (d,
J = 8.5 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 2.5 Hz, 1 H),
7.46 (d, J = 8.0 Hz, 1 H), 7.30–7.26 (m, 1 H), 7.20–7.17 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 140, 137.6, 136.3, 130.6, 130.4,
128.6, 126.9, 123.1, 120.9, 119.3, 111.5, 109.1. Anal. Calcd (%)
for C14H10ClNO2S: C, 57.63; H, 3.45; N, 4.80. Found: C, 57.65; H,
3.47; N, 4.82.
6-Chloro-2-(phenylsulfonyl)-1H-indole (3o)8a
White solid (116.7 mg, 80% yield); mp 181–183 °C. 1H NMR (500
MHz, CDCl3): δ = 9.01 (br s, 1 H), 8.01 (d, J = 8.5 Hz, 2 H), 7.55–
7.49 (m, 4 H), 7.24 (d, J = 7.5 Hz, 1 H), 7.09–7.06 (m, 2 H). 13C
NMR (125 MHz, CDCl3): δ = 141.9, 136.4, 133.9, 129.7, 128.2,
125.9, 124.8, 123.3, 121.2, 119, 111.7, 109. Anal. Calcd (%) for
2-[(4-Bromophenyl)sulfonyl]-1H-indole (3d)8a
White solid (142.9 mg, 85% yield); mp 191–193 °C. 1H NMR (500
MHz, CDCl3): δ = 8.87 (br s, 1 H), 7.71 (d, J = 8.5 Hz, 2 H), 7.50 (d,
J = 7.5 Hz, 1 H), 7.42 (d, J = 2.5 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 1 H),
7.19–7.18 (m, 3 H), 7.12–7.09 (m, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 140.5, 138.4, 136.3, 131.5, 130.6, 127.2, 123.1, 120.9,
119.3, 118.1, 111.5, 109. Anal. Calcd (%) for C14H10BrNO2S: C,
50.01; H, 3.00; N, 4.17. Found: C, 50.04; H, 3.01; N, 4.15.
2-[(4-Methoxyphenyl)sulfonyl]-1H-indole (3e)8a
C
14H10ClNO2S: C, 57.63; H, 3.45; N, 4.80. Found: C, 57.61; H,
3.47; N, 4.78.
7-Methyl-2-(phenylsulfonyl)-1H-indole (3p)1
White solid (130.2 mg, 96% yield); mp 171–173 °C. 1H NMR (500
MHz, CDCl3): δ = 8.97 (br s, 1 H), 7.98 (d, J = 8.0 Hz, 2 H), 7.61–
7.53 (m, 4 H), 7.20 (s, 1 H), 7.13–7.07 (m, 2 H), 2.50 (s, 3 H). 13
C
NMR (125 MHz, CDCl3): δ = 141.1, 136.2, 134.2, 131.8, 130.2,
129.4, 129, 126.2, 122.9, 120.7, 119.6, 111, 19.7. Anal. Calcd (%)
for C15H13NO2S: C, 66.40; H, 4.83; N, 5.16. Found: C, 66.37; H,
4.81; N, 5.15.
White solid (127.9 mg, 89% yield); mp 186–187 °C. 1H NMR (500
MHz, CDCl3): δ = 8.81 (br s, 1 H), 7.9 (d, J = 8.5 Hz, 2 H), 7.42 (d,
J = 2.5 Hz, 1 H), 7.31 (d, J = 8.5 Hz, 1 H), 7.09 (d, J = 7.5 Hz, 2 H),
7.06–7.03 (m, 2 H), 6.91 (d, J = 8.5 Hz, 1 H), 3.77 (s, 3 H). 13C
NMR (125 MHz, CDCl3): δ = 162.9, 136.4, 135, 131.2, 129.8,
128.5, 125.5, 124.5, 115, 113.4, 112.3, 108.6, 55.6. Anal. Calcd
(%) for C15H13NO3S: C, 62.70; H, 4.56; N, 4.87. Found: C, 62.72; H,
4.55; N, 4.89.
3-Methyl-2-(phenylsulfonyl)-1H-indole (3q)8d
White solid (120.7 mg 89% yield); mp 168–169 °C. 1H NMR (500
MHz, CDCl3): δ = 8.87 (br s, 1 H), 7.99 (d, J = 7.6 Hz, 2 H), 7.60–
7.49 (m, 4 H), 7.43–7.40 (t, J = 7.6 Hz, 2 H), 7.18–7.15 (t, J = 7.6
Hz, 1 H), 2.53 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 141.5,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

G
R. Rahaman, P. Barman
Letter
Synlett
136.2, 133.5, 129.4, 128.2, 127, 126.1, 122.2, 120.5, 119.6, 112.1,
111.4, 8.8. Anal. Calcd (%) for C15H13NO2S: C, 66.40; H, 4.83; N,
5.16. Found: C, 66.42; H, 4.80; N, 5.13.
H, 2.45; N, 3.78. Found: C, 45.39; H, 2.44; N, 3.75.
S-p-Tolyl-4-methylbenzenesulfonothioate (3aa)9f
White solid (194.9 mg 70% yield); mp 91–93 °C. 1H NMR (500
MHz, CDCl3): δ = 7.49 (d, J = 7.0 Hz, 2 H), 7.22–7.16 (m, 4 H),
7.14 (d, J = 7.0 Hz, 2 H), 2.36 (s, 3 H), 2.32 (s, 3 H).
1,2-Di-p-tolyldisulfane (3ab)9f
5-Bromo-2-[(4-chlorophenyl)sulfonyl]-1H-indole (3r)8b
Brown solid (127.8 mg, 69% yield); mp 183−186 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.85 (br s, 1 H), 8.02 (d, J = 7.0 Hz, 2 H),
7.81 (s, 1 H), 7.59 (d, J = 7.0 Hz, 2 H), 7.46 (d, J = 7.0 Hz, 1 H), 7.43
(d, J = 7.5, 1 H), 7.14 (d, J = 2.0 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 141.1, 140, 137.4, 136.3, 131, 130, 129.2, 129, 126.4,
115.8, 114.3, 108.5. Anal. Calcd (%) for C14H9BrClNO2S: C, 45.37;
White solid (36.8, mg 15% yield); mp 45–48 °C. 1H NMR (400
MHz, CDCl3): δ = 7.42 (d, J = 8.0 Hz, 4 H), 7.12 (d, J = 8.0 Hz, 2 H),
2.35 (s, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G