Microwave assisted metal-/oxidant-free cascade electrophilic sulfenylation/5-endo-dig cyclization of 2-alkynylanilines to generate diversified 3-sulfenylindoles

Article abstract of DOI:10.1016/j.tetlet.2017.08.046

A metal-/oxidant-free sustainable protocol for the synthesis of 3-sulfenylindoles based on electrophilic cyclization of 2-alkynylanilines has been developed under microwave irradiation. Herein, catalytic amount of iodine and stoichiometric amount of sulfonyl hydrazides were employed as catalyst and electrophiles respectively to induce the 5-endo-dig cyclization of 2-alkynylanilines. This strategy allows a wide substrate scope, demonstrates good functional group tolerance, utilizes easily available reagents and overcome multistep synthesis.

Full text of DOI:10.1016/j.tetlet.2017.08.046

Accepted Manuscript
Microwave assisted metal-/oxidant-free cascade electrophilic sulfenylation/ 5-
endo-dig cyclization of 2-alkynylanilines to generate diversified 3-sulfenylin-
doles
Shivani Sharma, Ramdas S. Pathare, Sukanya, Antim K. Maurya, Bhagyashree
Goswami, Vijai K. Agnihotri, Devesh M. Sawant, Ram T. Pardasani
PII:
S0040-4039(17)31053-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.046
TETL 49236
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 July 2017
18 August 2017
19 August 2017
Please cite this article as: Sharma, S., Pathare, R.S., Sukanya, Maurya, A.K., Goswami, B., Agnihotri, V.K., Sawant,
D.M., Pardasani, R.T., Microwave assisted metal-/oxidant-free cascade electrophilic sulfenylation/ 5-endo-dig
cyclization of 2-alkynylanilines to generate diversified 3-sulfenylindoles, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.08.046
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Microwave assisted metal-/oxidant-free
cascade electrophilic sulfenylation/ 5-endo-
dig cyclization of 2-alkynylanilines to
generate diversified 3-sulfenylindoles
Shivani Sharma,a Ramdas S Pathare,a Sukanya,b Antim K Maurya,c Bhagyashree Goswami,b Vijai K Agnihotri,c
Devesh M Sawant,b* Ram T Pardasania*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Microwave assisted metal-/oxidant-free cascade electrophilic sulfenylation/ 5-endo-
dig cyclization of 2-alkynylanilines to generate diversified 3-sulfenylindoles
Shivani Sharma,a Ramdas S Pathare,a Sukanya,b Antim K Maurya,c Bhagyashree Goswami,b Vijai K
Agnihotri,c Devesh M Sawant,b* Ram T Pardasania*
aDepartment of Chemistry, bDepartment of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Kishangarh –
305 817, Rajasthan, INDIA.
cNatural Product Chemistry and Process Development Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur-176 061, Himachal Pradesh,
INDIA
ARTICLE INFO
ABSTRACT
Article history:
Received
A metal-/oxidant-free sustainable protocol for the synthesis of 3-sulfenylindoles based on electrophilic
cyclization of 2-alkynylanilines has been developed under microwave irradiation. Herein, catalytic
amount of iodine and stoichiometric amount of sulfonyl hydrazides were employed as catalyst and
electrophiles respectively to induce the 5-endo-dig cyclization of 2-alkynylanilines. This strategy
allows a wide substrate scope, demonstrates good functional group tolerance, utilizes easily available
reagents and overcome multistep synthesis.
Received in revised form
Accepted
Available online
Keywords:
Microwave assisted organic synthesis;
5-endo-dig cyclization;
Iodine;
2009 Elsevier Ltd. All rights reserved.
Cascade;
3-sulfenylindole
(i) Various routes to organo-sulfur compounds
Cascade reactions are emerging as powerful chemical tool to
construct molecular complexity from simple precursors.1
R1
R1
R1 SR3
R2 Nu
A
Nu
R3
[S] sources
R2
(1)
(2)
sequential activation of C-C multiple bonds using electrophilic
sulphur sources to generate thiiranium ion intermediate,
following by its opening using various nucleophiles is an elegant
cascade strategy for accessing 1,2-difunctionalized products
[Eq(1)].2 Interestingly, the cascade strategy employed on the
substrates having nucleophilic partner tethered to the C-C
multiple bond would furnish bioactive 3-thiolated indoles and
benzofurans [Eq(2)]. The methodology has distinct advantages
over the conventional synthetic routes for 3-functionalized
indoles and benzofurans, such as (i) cross-coupling of vinyl/ aryl
halides with thiolating agents such as thiols, disulfides etc,3 (ii)
coupling of aryl- and alkyl lithium or Grignard reagents with
sulfenylating agents,4 and (iii) direct sulfenylation of C-H bond
using various sulfurating agents5 that required pre-functionalized
starting materials, harsher reaction conditions, and noxious and
unstable sulphur sources. The most extensively used electrophilic
sulphur sources for the activation of C-C multiple bond are the
arylsulfenyl chlorides6 and diaryl disulfides.7 However, these
methods required use of either expensive and air sensitive metal
catalysts and/or oxidants, and obnoxious, toxic and unstable
sulfur reagents. Hence, a direct and concise method based on
stable and environmentally friendly reagents would be highly
desirable to generate these organo-sulfur compounds. Recently,
sulfonyl hydrazides have emerged as cleaner, odourless and
stable source of sulfenylating agents to afford organo-sulfur
compounds.8
S
R2
R2
R3
S
R2
R3
S
X
R1
[S] sources
R2
R1
R1
XH
XH
where X = O, NH
(ii) Previous work
R2
S
R1
metal/ metal-free
metal/ metal-free
(3)
(4)
R1
[S] sources
R2
N
H
N
H
R3
R2
S
R1
[S] sources
R1
NX2
N
X
where X = H, Me
(iii) This work
I2 (10 mol%)
TsOH (50 mol%)
Dioxane, 110 o
R3
R2
R3SO2NHNH2
S
p
(5)
C
R2
R1
R1
MW (100W)
N
NH2
1equiv
H
1.5 equiv
Scheme 1: Different strategies to construct 3-sulfenylindoles

2
Tetrahedron
Table 1: Optimisation of reaction Conditions
entry
I2
additive
t (h)
T
(oC)
Solvent
Isolated
(mol%)
(50 mol%)
Yield (%)
1.
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
-
24
70
EtOH
EtOH
-
2.
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
AcOH
24
110
110
110
120
120
110
110
110
110
110
110
110
110
110
110
110
80
45
10
48
64
-
3.
24
H O
2
4.
24
DCE
5.
24
Toluene
6.
24
DMF
7.
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
82
85a
8.
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.50
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
a
9.
-
a
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
CF3CO2H
TfOH
-
23a
42a
39a
PhCO2H
(COOH)2
PhH2PO2
Ca(OTf)2
Sc(OTf)2
In(OTf)2
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
a
-
74a
69a
62a
43a
140
110
110
110
110
110
110
110
110
31a
70a
1
tracesa
72a,d
50a,e
64a,b
86a,c
61f,h
48g,i
10
10
10
10
10
10
Reaction condition: 1a (1.0 mmol), 2b (1.5 mmol), additive (50 mol%),
solvent (1 mL). aMW (100W), b1.0 mmol of 2b, c2.0 mmol of 2b, d30 mol%
g
of pTsOH, e10 mol% of pTsOH was employed, fMW (80W), MW (150W),
h30% Starting material recovered, imultiple spots observed .
Scheme 2: Substrate scope of sulfonyl hydrazides
The indole is a privileged heterocycle found in a spectrum of
natural products and pharmacologically active compounds.9 Of
these, 3-sulfenylindoles are important class of compounds that
possess pharmacological activity against various diseases such as
HIV,10 neuroleptic,11 allergies,12 cardiovascular,13 obesity14 and
cancer.15 In general, 3-sulfenylindoles are synthesized by direct
sulfenylation of indoles16 [Eq (3)] or via transition-metal
catalysed (or oxidant mediated) annulation of 2-(1-
alkynyl)aniline6,7 [Eq (4)] using various sulfenylating agents.
Recently, the effective synthetic strategies have been developed
to access these 3-sulfenylindoles using sulfonyl hydrazides as
sulfenylating agents.17 Since electrophilic aryl sulfenyl
intermediate is generated in situ from the reaction of iodine and
sulfonyl hydrazides, therefore this strategy could be elegantly
applied for the cascade electrophilic sulfenylation/ 5-endo-dig
cyclization to furnish 3-sulfenylindoles. Very recently, Kahukarn
et al.18 reported synthesis of the N-alkyl-3-sulfonylindoles and N-
alkyl-3-sulfanylindoles by cascade annulation of 2-alkynyl-N,N-
dialkylaniline using excess of sulfonyl hydrazides as sulphur
source. But this strategy was limited to 2-alkynyl-N,N-
dialkylaniline, with the requirement of stoichiometric amount of
iodine. In continuation of our interest in generating bioactive
heterocycles,19 we report herein metal or oxidant free cascade
electrophilic sulfenylation/ 5-endo-dig cyclization of 2-
alkynylanilines under microwave irradiation using catalytic
amount of molecular iodine [Eq (5)]. The combination of cascade
strategy with microwave assisted organic synthesis (MAOS),20 is
considered as a sustainable synthetic approach because of
shorten reaction time and minimal side products.
Initially, our investigation began by reacting 2-alkynylaniline
1a with p-tolylsulfonyl hydrazines 2b (2.0 equiv) and iodine (10
o
mol%) in ethanol at 70 C as reported by Tian et al.17a However,
no conversion occurred at this temperature and 1a was recovered
as such (entry 1, table 1). Fortunately, increasing the temperature
o
of the reaction mixture to 110 C and use of p-TsOH21 resolved
this problem (entry 2) and furnished the desired 3-sulfenylindoles

3
Ph
TsNHNH2
S
Standard
Condition
(a)
Ph
N
NH2
H
1a
2b
3ab
Condition
none
TEMPO
galvinoxyl
85%
81%
79%
I2 (10 mol%)
pTSA (0.5 equiv)
Ph
(b)
Ph
dioxane, 110 o
MW (100W)
C
N
H
NH2
1a
4a (0%)
Scheme 4: (a) Radical trap (b) control experiment
Next, a series of 2-alkynylanilines were evaluated using
different substituents at the terminal alkyne moiety of 2-
alkynylanilines (Scheme 4). Both electron donating and electron
withdrawing substituents at the phenyl ring were well compatible
(3ba-3be). The electron withdrawing substituents were dominant
over the electron donating substituents. Gratifyingly, substrates
containing substituents such as Cl, CN on corresponding aniline
ring, also underwent annulation reaction with sulfonyl hydrazides
under standard reaction conditions to afford desired products
(3ca- 3cc) in good yields, which could be used for further
transformation. This protocol was also applicable to 2-thienyl
moiety (3da). Moreover, aliphatic group at the terminal alkyne
moiety of 2-alkynylaniline also underwent annulation (3ea and
3ga) smoothly.
In order to gain insights into the reaction mechanism, radical
scavenger experiment was carried out under standard conditions
[Scheme 4(a)]. The addition of radical scavengers such as
TEMPO and galvinoxyl could not alter the formation of 3ab,
demonstrating that a non-radical pathway was involved in the
reaction. Intermediacy of 2-phenylindole was ruled out by
carrying out reaction of 2-alkynylaniline 1a under standard
condition in the absence of 2b. This clearly indicated the cascade
Scheme 3: Substrate scope of 2-alkynylanilines
3ab in 45% isolated yield in 24 hrs. Next, a series of solvents
were explored (entries 3-7) and 1,4-dioxane showed a better
result compared to ethanol. Consequently, it was observed that
microwave irradiation could rapidly facilitate this transformation
with minimal reaction time and maximal product yield (entry 8).
Explorations with different Brønsted and Lewis acids revealed
that a Ca(OTf)2 afforded maximum yield upto 74% (entries 9-
17), but p-TsOH was the best choice. Lowering of reaction
temperature prolonged the reaction time with reduced yield
(entry 18). However, increasing the temperature had detrimental
effect on the outcome of reaction (entry 19). Finally the effect of
catalyst loading and equivalence of 2b were investigated. The
best result was observed when 1 equiv of 2b was reacted with 1a
(1.5 equiv) using 10 mol% of iodine and 0.5 equiv of p-TsOH in
electrophilic sulfenylation/
cyclization [Scheme 4(b)].
intramolecular
nucleophilic
On the basis of mechanistic investigation and literature
precedence,17a,21 the plausible mechanism is proposed as depicted
in Scheme 5.
o
1,4-dioxane at 110 C under microwave irradiations for 15 min
furnishing 3ab in 85% isolated yield.
With the optimized reaction conditions in hand, the generality
and substrate scope of sulfonyl hydrazides were investigated and
the results are shown in Scheme 2. Both electron withdrawing
and electron donating substituents bearing aryl sulfonyl
hydrazides underwent sulfenylation to afford the corresponding
indole thioethers (3ab-3aj) in moderate to good yields. Even
benzylsulfonylhydrazide worked efficiently (3ak). However,
aliphatic sulfonyl hydrazides such as camphor and octylsulfonyl
hydrazide afforded none of the desired products. Thus, it
emerged that electronic parameters play significant role in the
reaction pathway. Notably, heteroaromatic 2-thienyl also reacted
smoothly to furnish 3al in 70 % yield.
Scheme 5: Plausible reaction mechanism

4
Tetrahedron
7. (a) Guo Y-J, Tang R-Y, Li J-H, Zhong P, Zhang X-G, Adv. Synth.
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C-L, Liu Y, Li J-H, Zhang XG, Adv. Synth. Catal. 2011; 353:
2739.
Initially, the oxidation of sulfonyl hydrazide 2 with iodine
leads to intermediate 5, which under acidic condition forms
intermediate 6 and TsOI. The intermediate 6 then undergoes self
double dehydration using TsOH as a catalyst to afford
thiodiazonium species 9 which may generate intermediate 10
with the liberation of N2. Finally, thiodiazonium species 9 or
intermediate 10 upon electrophilic addition to alkyne 1 gives
thiirenium ion 11 which upon intramolecular ring opening via
amino group produces the desired product 3. HI and TsOI, in situ
by-products reacted with each other to regenerate the I2 and
TsOH.
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S, Kandikere NV, Kota S, Jasti V, PCT Int. Appl. WO
2007020653, 2007.
In summary, a microwave assisted strategy has been developed
for the synthesis of 3-sulfenylindoles via metal-/oxidant free
cascade electrophilic sulfenylation/ intramolecular nucleophilic
cyclization of 2-alkynylanilines with sulfonyl hydrazides. The
methodology reported herein demonstrates high substrate scope
and excellent functional group tolerance. The methodology
proceeded without any metal and oxidant under microwave
irradiation, which made this transformation sustainable and
environmently benign. The byproducts (TsOH and I2) reacted
with each other to regenerate the catalytic system. Further
mechanistic investigation and their significant utility in a variety
of synthetic application are the future prospective of this work.
15. Regina GL, Elder MC, Brancale A, Kandil S, Coluccia A,
Piscitelli F, Hamel E, Martino GD, Matesanz R, Diaz JF, Scovassi
AI, Prosperi E, Lavecchia A, Novellino E, Artico M, Silverstri R,
J. Med. Chem. 2007, 50: 2865.
16. (a) Fang X-L, Tang R-Y; Zhong P, Li J-H Synthesis 2009, 24:
4183; (b) Prasad CD, Kumar S, Sattar M, Adhikary A, Kumar S,
Org. Biomol. Chem. 2013, 11: 8036; (c) Wu Z, Li Y-C, Ding W-
Z, Zhu T, Liu SZ, Ren X, Zou L-H, Asian J. Org. Chem. 2016, 5:
625.
Acknowledgments
17. (a) Yang F-L, Tian, S-K, Angew. Chem. Int. Ed. 2013, 52: 1; (b)
Rahaman R, Devi N, Sharma K, Barman P, RSC Adv. 2016, 6:
10873; (c) Yang Y, Zhang S, Tang L, Hu Y, Zha Z, Wag Z, Green
Chem. 2016, 18: 2609.
We are grateful to CSIR [Grant No. 02(0201)/14/EMR-II] and
DST [Grant No. SB/FT/CS-012/2014 and FIST grant
SR/FST/CSI-257/2014(c)] for funds and fellowship to SS and
RSP respectively.
18. Meesin J, Pohmakotr M, Reutrakul V, Soorukram V, Leowanawat
P, Kuhakarn C, Org. Biomol. Chem. 2017, 15: 3662.
19. (a) Sharma S, Pathare RS, Maurya AK, Gopal K, Roy TK,
Sawant DM, Pardasani RT, Org. Lett. 2016, 18: 356; (b) Sharma
S, Singh S, Kumari A, Sawant DM, Pardasani RT, Asian J. Org.
Chem. 2017, 6: 726; (c) Pathare RS, Sharma S, Kandaswamy G,
Sawant DM, Pardasani RT Tetrahedron Lett. 2017, 58: 1387; (d)
Pathare RS, Sharma S, Elagandula S, Saini V, Sawant DM, Yadav
M, Sheoran A, Khan S, Pardasani RT, Eur. J. Org. Chem. 2016,
5579.
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X-T, Tian S-K, Chem. Eur. J. 2012, 18: 1582.
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Supplementary Material
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5
Microwave assisted metal-/oxidant-
free cascade electrophilic
sulfenylation/ 5-endo-dig cyclization of
2-alkynylanilines to generate
diversified 3-sulfenylindoles
Shivani Sharma,a Ramdas S Pathare,a Sukanya,b
Antim K Maurya,c Bhagyashree Goswami,b Vijai K
Agnihotri,c Devesh M Sawant,b* Ram T Pardasania*
aDepartment of Chemistry, bDepartment of Pharmacy, School of Chemical
Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri,
Kishangarh – 305 817, Rajasthan, INDIA.
cNatural Product Chemistry and Process Development Division, CSIR-
Institute of Himalayan Bioresource Technology, Palampur-176 061,
Himachal Pradesh, INDIA
Highlights:
1. Metal-/oxidant-free approach to 3-
sulfenylindoles
irradiation
under
microwave
2. Use of catalytic amount of I2 and
stoichiometric amount of sulfonyl
hydrazides
3. Broad
substrate
scope,
excellent
functional group tolerance
4. Shorter reaction time with minimal side
products