Green synthesis of benzo[b]thiophenes via iron(III) mediated 5-endo-dig iodocyclization of 2-alkynylthioanisoles

Article abstract of DOI:10.1016/j.tetlet.2015.12.037

A reaction of iron(III) chloride with sodium iodide was used to generate iodine for an innovative take on electrophilic cyclization. With ethanol as solvent, the reaction was observed to provide ideal conditions for iodocyclization of 2-alkynylthioanisole

Full text of DOI:10.1016/j.tetlet.2015.12.037

Tetrahedron Letters 57 (2016) 411–414
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Tetrahedron Letters
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Green synthesis of benzo[b]thiophenes via iron(III) mediated
5-endo-dig iodocyclization of 2-alkynylthioanisoles
⇑
Tanay Kesharwani , Cory T. Kornman, Amanda L. Tonnaer, Andrew D. Royappa
Department of Chemistry, University of West Florida, Pensacola, FL 32514-5750, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A reaction of iron(III) chloride with sodium iodide was used to generate iodine for an innovative take on
electrophilic cyclization. With ethanol as solvent, the reaction was observed to provide ideal conditions
for iodocyclization of 2-alkynylthioanisoles. The fundamental step allows formation of iodine which
becomes free to undergo reaction with the starting alkyne to yield the cyclized product. Implementing
environmentally benign and simple chemistry, 2-iodosubstituted benzo[b]thiophenes were synthesized
in high yields to produce an interesting display of useful molecules.
Received 12 November 2015
Accepted 8 December 2015
Available online 9 December 2015
Keywords:
Green chemistry
Electrophilic cyclization
Iodocyclization
Ó 2015 Elsevier Ltd. All rights reserved.
Benzo[b]thiophene
Iron(III) mediated
Electrophilic cyclization is a reaction sequence which involves
cyclization of an unsaturated C–C bond onto an internal
nucleophilic carbon or heteroatom in the presence of an external
electrophile.1 In the past decade reactions involving alkynes having
a variety of nucleophilic attachments such as carbon,2 oxygen,3
nitrogen,4 sulfur,5 selenium6 and tellurium6e have been
extensively investigated. A variety of electrophilic agents may be
employed to synthesize a diverse library of biologically active
molecules. In such processes the most commonly used
electrophiles are I2, ICl, Br2, NBS and PhSeBr.1–6 Examples of other
toxic and thus pose unnecessary risks to the chemist and to the
environment.
Iron salts are not only environmentally friendly but abundantly
available. Furthermore, many iron salts and related complexes are
inexpensive and easily obtainable from commercial sources.
Despite the above-mentioned advantages, iron mediated reactions
have been underrepresented for a long time until recent work
involving several interesting iron mediated processes was intro-
duced.13 With this in mind, we report a more benign process for
the synthesis of various 3-iodobenzo[b]thiophenes via iron(III)
mediated 5-endo-dig electrophilic iodocyclization of 2-alkyny-
lthioanisoles in ethanol (Scheme 1).
electrophiles such as TCCA,7 NIS,8 p-NO2C6H4SCl,2d,3b,4c,d CuCl2
9
9b,c
and CuBr2
are also known. In a competitive study Larock and
co-workers have demonstrated that more nucleophilic atoms,
such as S or Se, work better in electrophilic cyclization reactions
when compared with C, O and N nucleophiles.10
It was determined that substituted 2-alkynylthioanisoles in the
presence of iron(III) chloride hexahydrate and sodium iodide
underwent electrophilic iodocyclization to form 2,3-disubstituted
benzo[b]thiophene derivatives in high yields of up to 97%. This
room temperature, single-step methodology eliminates the need
for harsh solvents or direct contact with halogen cyclizing agents
thus allowing for a greener electrophilic synthesis.
The desired starting alkynes (1–12) were synthesized using pro-
cedures reported in recent literature.5e,14 The Sonogashira coupling
of 2-iodothioanisole with terminal alkyne in presence of copper
iodide and palladium catalyst proceeded at room temperature
and furnished excellent yields. Alkyne 13 was synthesized by
deprotection of TMS group in compound 7.15
Benzo[b]thiophenes are naturally occurring11 sulfur containing
heterocycles that provide the core structure for many biologically
active molecules12 and commercially available drugs (Fig. 1).
Therefore they are of great interest to both synthetic and medicinal
chemists. Recently reported syntheses of benzo[b]thiophenes via
electrophilic 5-endo-dig iodocyclization have been known to use
less-friendly solvents such as acetonitrile and dichloromethane,
and employ electrophilic reagents such as iodine, bromine and
phenyl selenium bromide. While synthetically useful, electrophilic
reagents such as iodine and bromine are volatile, corrosive and
To determine the scope of this method, a variety of functional-
ized 2-alkynylthioanisoles were cyclized via our standard reaction
procedure as described in Scheme 1. Substituted 2-alkyny-
lthioanisoles (1 equiv) were reacted in the presence of iron(III)
⇑
Corresponding author. Tel.: +1 850 474 2743.
E-mail address: tkesharwani@uwf.edu (T. Kesharwani).
http://dx.doi.org/10.1016/j.tetlet.2015.12.037
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

412
T. Kesharwani et al. / Tetrahedron Letters 57 (2016) 411–414
N
O
H
O
CH3
N
N
NH2
S
OMe
S
S
HO
O
HO
Zileuton
Benocyclidine
Arzoxifene
Cl
N
N
O
O
N
O
HN
N
Cl
OH
S
O
S
HO
S
Cl
Cl
Encenicline
Raloxifene
Sertaconazole
Figure 1. Drug molecules containing benzo[b]thiophene core structure.
chloride hexahydrate (1.2 equiv) and sodium iodide (2.4 equiv) in
95% ethanol at room temperature for twelve hours. Reaction mix-
tures were monitored to completion via TLC before purification via
column chromatography.16
SMe
S
NaI, FeCl3•6H2O
r.t., EtOH
R
I
R
A molecular library of 2-iodo substituted benzo[b]thiophene
derivatives were prepared using our methodology (Table 1). Start-
ing with simple aromatic phenyl and p-tolyl substituents (entries 1
and 2) on the alkyne, this reaction proceeded with respective
yields of 93% and 97%. However, electron rich p-methoxy phenyl
substituted alkyne 3 resulted in 16 in a slightly lower yield of
1-13
R = alkyl, aryl, vinyl
14-25
Yield 48-97%
Scheme 1. Iron(III) mediated electrophilic iodocyclization.
Table 1
5-endo-Dig cyclization/etherification of 2-alkynlythioanisoles to corresponding 3-iodosubstituted benzo[b]thiophenesa
Entry
Substrate
SMe
Product
% Yieldb
S
1
1
2
14
15
93
I
SMe
SMe
SMe
S
Me
2
97
I
Me
S
OMe
3
4
3
4
16
17
89
93
I
OMe
S
I
SMe
SMe
S
n-Bu
t-Bu
5
6
5
6
18
19
93
92
I
n-Bu
S
I
-Bu
t

T. Kesharwani et al. / Tetrahedron Letters 57 (2016) 411–414
413
Table 1 (continued)
Entry
Substrate
SMe
Product
% Yieldb
S
SiMe3
7
8
7
20
21
92
86
I
SiMe3
OH
SMe
SMe
OH
OH
S
8
9
I
S
OH
I
9
22
17
48
83
SMe
S
10
10
OH
I
SMe
SMe
OMe
S
11
12
11
12
23
24
97
96
OMe
I
S
(CH2)3CN
I
(CH2)3CN
SMe
S
H
13
13
25
56
I
H
a
Reaction condition A: All reactions were performed on a 0.3 mmol scale using 1.0 equiv of alkyne, 1.2 equiv of FeCl3Á6H2O, and 2.4 equiv of NaI in 4 mL of ethanol at room
temperature for 24 h.
b
Isolated yields.
SMe
FeCl3 + NaI
S
Me
S
NaX, FeCl3•6H2O
r.t., EtOH
Me
S
I2
X
+
I
14
X = I
26 X = Br
27 X = Cl
90%
0%
0%
Ph
Ph
1
I
Ph
Ph
1
28
14
I
Scheme 2. Effect of various sodium halides on electrophilic cyclization.
Me
S
S
I
- MeI
89% (entry 3). Iodocyclization of vinyl substituted alkyne 4 fur-
nished the desired cyclized product 17 in a very high yield of 93%.
Simple n-butyl and bulky tert-butyl substituted alkynes 5 and 6
resulted in desired cyclized products 18 and 19 in almost identical
yield (entries 5 and 6) suggesting that the bulky group had no or
minimal effect on the incoming electrophile during the cyclization
reactions. The sterically demanding TMS group worked well and
provided benzo[b]thiophene 20 in 92% yield, once again supporting
our previous observation (entry 7).
I
29
Scheme 3. Proposed mechanism of iodocyclization involving FeCl3 and NaI.
also accomplished the cyclization of a terminal alkyne (13) with
our conditions, which was not reported in earlier iodocyclization
methodologies (entry 13).
Primary propargylic alcohol 8 worked well and resulted in 86%
yield of the cyclized product 21. However, secondary propargylic
alcohol 9 resulted in lower yield of the product 22. Propargylic
alcohol 10 underwent iodocyclization with an elimination mecha-
nism to yield cyclized benzo[b]thiophene 17 in 83% yield. This
novel method of dehydration makes an interesting candidate for
future research possibilities. Our reaction conditions also seem to
tolerate ether and nitrile functionalities (entries 11 and 12). We
Recently we have reported an environmentally friendly method
for the synthesis of 3-halosubstituted benzo[b]thiophenes using
CuSO4Á5H2O in ethanol at ambient temperature.14a Upon
consideration, however, the use of the relatively toxic metal
copper in lieu of less toxic iron salts may limit the large-scale
applications of this method. However, the former methodology
supports bromo- and chlorocyclizing agents whereas the latter
only supports iodocyclization methods (Scheme 2). Even though

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the present iron(III) chloride methodology is more limited than the
wider tolerance shown by the copper sulfate method, it is
compensated for by more benign reaction conditions and
comparatively higher yields.
While understanding of FeCl3/NaI mediated cyclization requires
additional studies,
a reasonable mechanism is proposed in
Scheme 3. We believe elemental iodine is generated within the
reaction mixture via reaction of iron(III) chloride and sodium
iodide. As shown in Scheme 3, an in situ-generated iodine cation
coordinates with the unsaturated carbon–carbon triple bond form-
ing an iodonium cation (28). The tethered sulfur atom acts as a
nucleophile to attack and open the three-membered ring contain-
ing the iodonium cation, resulting in 5-endo-dig ring-closure, form-
ing the charged intermediate 29. Lastly, the iodide anion attacks
the methyl group through an SN2 mechanism, to lose the desired
benzo[b]thiophene derivative 14 as a leaving group.
In summary, we have developed an environmentally friendly
alternative for the electrophilic cyclization reaction sequence.
5-endo-Dig cyclization of 2-alkynylthioanisoles proceeded in high
yields to form an interesting library of potentially useful benzo
[b]thiophene derivatives. In addition to reducing harmful waste
and byproducts, this green process proceeds at room temperature,
demonstrates functional group tolerance and results in excellent
yields of the desired product. Our process provides a clean and
simple method for the synthesis of many benzo[b]thiophene
derivatives.
Acknowledgments
We are grateful to Research Corporation for Science Advance-
ment for a Cottrell College Science Award, and the University of
West Florida (UWF) and UWF’s Office of Research and Sponsored
Programs for supporting this research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.12.
037.
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16. General procedure for the synthesis of compounds 14–25. To a 6-dram vial
containing starting alkyne (0.30 mmol), 5 mL 95% ethanol was added. To the
mixture, FeCl3Á6H2O (100 mg, 0.37 mmol) and sodium iodide (111 mg,
0.74 mmol) were added. The reaction mixture was allowed to stir at room
temperature for 24 h. The reaction mixture was concentrated, absorbed in
silica gel and purified via column chromatography using hexanes to ethyl
acetate mixture as eluent.
3-Iodo-2-phenylbenzo[b]thiophene (14). Product was isolated as a pale yellow
oil; 1H NMR (400 MHz, Chloroform-d) d 7.40 (t, J = 7.6 Hz, 1H) 7.44–7.53
(m, 4H) 7.70 (d, J = 7.2 Hz, 2H) 7.80 (d, J = 8.0 Hz, 1H) 7.85 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, Chloroform-d) d 79.6, 122.3, 125.6, 125.7, 126.5, 128.7,
129.0, 130.2, 134.8, 139.1, 142.1, 142.4. HRMS (EI+, m/z) calcd for (C14H9IS)+
335.9470, found 335.9473.