Green synthesis of halogenated thiophenes, selenophenes and benzo[b]selenophenes using sodium halides as a source of electrophilic halogens

Article abstract of DOI:10.1016/j.tetlet.2017.01.007

Herein, we report the first synthesis of chlorinated benzo[b]selenophenes via environmentally friendly electrophilic chlorocyclization reaction using “table salt” as a source of “electrophilic chlorine” and ethanol as a solvent. In addition, the synthesis

Full text of DOI:10.1016/j.tetlet.2017.01.007

Accepted Manuscript
Green Synthesis of Halogenated Thiophenes, Selenophenes and Benzo[b]sele-
nophenes Using Sodium Halides as a Source of Electrophilic Halogens
Tanay Kesharwani, Krystal A. Giraudy, Jordan L. Morgan, Cory Kornman,
Abayomi D. Olaitan
PII:
S0040-4039(17)30007-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.007
TETL 48510
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 November 2016
29 December 2016
2 January 2017
Please cite this article as: Kesharwani, T., Giraudy, K.A., Morgan, J.L., Kornman, C., Olaitan, A.D., Green Synthesis
of Halogenated Thiophenes, Selenophenes and Benzo[b]selenophenes Using Sodium Halides as a Source of
Electrophilic Halogens, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.007
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Green Synthesis of Halogenated Thiophenes,
Selenophenes and Benzo[b]selenophenes
Using Sodium Halides as a Source of
Electrophilic Halogens
Leave this area blank for abstract info.
Tanay Kesharwani,* Krystal Giraudy, Jordan Morgan, Cory Kornman and Abayomi D. Olaitan

1
Tetrahedron Letters
Green
Benzo[b]selenophenes Using Sodium Halides as a Source of Electrophilic Halogens
Synthesis
of
Halogenated
Thiophenes,
Selenophenes
and
Tanay Kesharwani,* Krystal A. Giraudy,† Jordan L. Morgan, Cory Kornman and Abayomi D. Olaitan
Department of Chemistry, University of West Florida, Pensacola, FL 32514-5750
ARTICLE INFO
ABSTRACT
Article history:
Received
Herein, we report the first synthesis of chlorinated benzo[b]selenophenes via environmentally
friendly electrophilic chlorocyclization reaction using “table salt” as a source of “electrophilic
chlorine” and ethanol as a solvent. In addition, the synthesis of diverse halogenated heterocycles,
including 3-chloro, 3-bromo and 3-iodo thiophenes, selenophenes, and benzo[b]selenophenes
was successfully accomplished under the same environmentally benign reaction conditions. This
methodology has several advantages over other previously reported reactions as it employs
simple starting compounds, an environmentally friendly solvent, ethanol, and non-toxic
inorganic reagents under mild reaction conditions, resulting in the high product yields.
Received in revised form
Accepted
Available online
Keywords:
Benzo[b]selenophene
Thiophene
2009 Elsevier Ltd. All rights reserved.
Selenophene
Electrophilic halocyclization
Green Chemistry
Sulfur and selenium-containing heterocycles have diverse
potential applications in drug discovery, pharmacology, optics,
electronics, material science, and so on. Thiophene is a
commonly used core structure in pharmaceutical drugs (Figure
1).1 Thiophene-containing molecules are known to exhibit
antimicrobial,2 non-steroidal anti-inflammatory,3 platelet
inhibitory,4 antitumor,5 and antiviral activity.6 In addition,
thiophenes are also used in polymers and materials that have a
potential application in the area of organic field-effect transistors
(OFETs) and organic light-emitting diodes (OLEDs).7–13
Selenophenes, a selenium analogue of thiophene, are also known
to exhibit biological activities, such as anticancer,14 antitumor,15
antidepressant,16 antioxidant,17 and antiproliferative activities.18
Benzo[b]selenophenes and selenophenes have a narrow HOMO-
LUMO gap when compared with their sulfur analogues and have
applications in photonics.19
Figure 1. Commercially available drugs containing the thiophene core
structure.
The introduction of a halogen atom at specific position(s) on
organic molecules not only serves as a reactive handle, but also
alters its structural, synthetic, biological, and pharmacological
properties, thereby further increasing the demands of halogenated
heterocycles.20 Over eighty percent of manufactured drugs are
synthesized using or containing halogens due to their versatility
and applications.21 In the past decade, electrophilic
halocyclization has emerged as an effective route of introducing
iodine and bromine moiety in the heterocycles.22 However, there
are only a few reported examples of introducing chlorine via
chlorocyclization reactions.23 Most of these chlorocyclization
reactions lack generality, require harsh reaction conditions, give
poor to moderate yields and utilize toxic reagents and solvents.
Scheme 1. Halogenated thiophenes, selenophenes and benzo[b]selenophenes
via copper-mediated halocyclization.
Herein we describe an environmentally benign process for the
synthesis of diverse halogenated thiophenes, selenophenes, and
benzo[b]selenophenes, which enables further functionalization of
̴̴̴̴̴̴̴̴̴̴̴ꢀ
ꢀ
ȗ Corresponding author. Tel.: +1 850-474-2743
E-mail address: tkesharwani@uwf.edu (T. Kesharwani).

2
Tetrahedron Letters
these heterocyclic molecules (Scheme 1). Most prominently, rare
chlorocyclization was successfully accomplished in diverse
heterocyclic systems with this method along with bromo- and
iodocyclization. It should be noted that this is the first report on
the synthesis of 3-chlorobenzo[b]selenophenes via electrophilic
chlorocyclization. This is the only reported reaction condition
where all three halogens (I, Br, and Cl) can be incorporated in the
same heterocyclic compound by only changing the sodium
halides as a source of electrophilic halide. Hence, our reaction
conditions have a potential to be applied towards the synthesis of
diverse heterocycles due to its generality. Our environmentally
benign method employs ethanol as a solvent (as opposed to
halogenated and toxic solvents used in earlier reported
methodologies), along with safe, inexpensive, and readily
available inorganic reagents, such as copper (II) sulfate
pentahydrate, and sodium halides, notably table salt for
chlorocyclization reactions. This method requires mild reaction
conditions resulting in very high yields of the products as
compared with earlier reports.23b,24
of 59% and 54%, respectively (Scheme 2, Eq. 1). Similarly, alkyl
and vinyl enyne substrates 7 and 8 were obtained in 35% and
29% yields, respectively. Enyne 9, the precursor to the synthesis
of 3-haloselenophene, was obtained by changing Me2S2 to
Bn2Se2, but otherwise the same procedure was followed as
described above (Scheme 2, Eq. 2).
Scheme 2. Synthesis of thiophene and selenophene precursors.
It was determined that the starting alkynes 5-9 and 12 in the
presence of a sodium halide, ethanol, and copper (II) sulfate
pentahydrate underwent electrophilic cyclization to form
thiophene, selenophene, and benzo[b]selenophene derivatives
with yields as high as 95% (Scheme 1). This methodology
utilizes the principles of green chemistry; thus, eliminating the
use of harsh solvents and cyclizing agents to create simpler and
cleaner electrophilic cyclization reactions. In addition, the
multiple electrophilic halocyclizations can be accomplished using
the same reactants by simply changing the employed sodium
halide. The only shortcoming of our methodology is the use of
excess CuSO4•5H2O. Our efforts to reduce the quantity of
CuSO4•5H2O failed and using less than 5 equivalents Cu salt
resulted in significantly lower yields of the products.25 Employing
solvents such as toluene and DMSO resulted in no reaction,
where as DMF, DCM, THF and nitromethane resulted in lower
yields of the product.
The two-step process for the preparation of alkyne 12, the
starting compound for benzo[b]selenophene synthesis, began
with Sonogashira coupling of 1-bromo-2-iodobenzene (10) with
phenylacetylene. The resulting alkyne 11, when subjected to a
lithiation halogen exchange reaction followed by the addition of
Bn2Se2 resulted in the formation of alkyne 12 with a 63% overall
yield for the two steps.
Scheme 3. Synthesis of benzo[b]selenophene precursor.
To further study the scope of our methodology, alkynes 5, 6,
9 and 12 were treated with a sodium halide, ethanol, and
Cu2SO4•5H2O. All cyclizations were monitored by means of thin
layer chromatography and the reaction mixtures were purified via
column chromatography.
The desired precursors for the synthesis of 3-halothiophenes were
obtained via a stereoselective method, previously reported in the
literature for producing alkylthio-1,4-diaryl-1-buten-3-yne. 1,3-
Phenyl and 3-thienyl diynes 1-2 when reacted with methyl
disulfide and NaBH4 formed enynes 5 and 6 in moderate yields
Table 1. Synthesis of halogenated thiophenes, selenophenes and benzo[b]selenophenes via green electrophilic cyclization a
Entry
Alkyne
Sodium Halide
Product
% yieldb
% lit yieldc
1
NaCl
92
65d
5
13
2
3
NaBr
NaI
86
90
72d
5
5
14
15
82e

3
4
NaCl
NaBr
NaI
91
-
-
6
6
6
9
9
9
16
17
18
19
20
21
5
6
7
8
9
-
91
81
92
95
-
NaCl
NaBr
NaI
70d
81d
93e
10
11
NaCl
NaBr
72
73
-
12
12
22
23
75f
12
NaI
62
90f
12
24
a Reaction Condition A: All reactions were performed using 0.30 mmol of the alkyne, 5 equiv of NaX, and 5 equiv of CuSO4•5H2O in 5 mL of EtOH at room
temperature for 24 h.b Isolated yields. c Literature yield via halocyclization. d reference 23b. e reference 24. f reference 26
Cyclization of the starting phenyl-substituted vinyl methyl
thiol 5 resulted in the desired 3-halothiophene products 13-15
with excellent yields of 92%, 86%, and 90%, respectively (Table
1, entries 1-3). Our greener and milder reaction conditions
resulted in the higher yields of chloro-, bromo-, and iodocyclized
an excellent yield of 91% (Table 1, entry 6). This is the first
report of the synthesis of chloro- and iodo-substituted
oligothiophenes 16 and 18, which are difficult to synthesize and
may have potential application in OLEDs and OFETs.
The eneyne 9, a selenium analogue of alkyne 5, when
subjected to the same cyclization conditions furnished the desired
chloro-, bromo-, and iodoselenophene products 19-21, in high
yields of 81%, 92%, and 95%, respectively (Table 1, entries 7-9).
Once again chloro- and bromocyclized products were obtained
by our method in higher yields compared to the methodology
reported by others23b,24 indicating the superiority of our reaction
conditions.
23b,24
products compared to an earlier reported methodology.
Replacing the phenyl group with a 3-thienyl moiety in the
starting vinyl methyl thiol resulted in the cyclized
chlorothiophene product 16 with an excellent yield of 91%
(Table 1, entry 4). Our efforts to synthesize bromothiophene 17
failed, as cyclization of enyne 6 with NaBr and Cu2SO4•5H2O
resulted in a complex reaction mixture. When NaBr was replaced
with NaI, the resulting iodocyclized product 18 was obtained in

4
Tetrahedron
Even though the bromo- and iodocyclization of 2-
In summary, we reported the first synthesis of 3-
chlorobenzo[b]selenophene via electrophilic chlorocyclization
reaction in good yields. In addition, this environmentally benign
high-yielding method was further used for the synthesis of
biologically and materially useful halogenated thiophenes and
selenophenes. This methodology has several advantages over
other previously reported reactions as it employs simple starting
compounds, an environmentally friendly solvent, ethanol and
non-toxic inorganic reagents under mild reaction conditions,
resulting in high product yields.
alkynylmethylselenobenzene has already been reported, there is
no reported example of chlorocyclization.26 Herein we disclose
the first ever report of this chlorocyclization reaction starting
with 2-alkynylmethylselenobenzene 12 using table salt and the
green solvent ethanol (Table 1, entry 10). The resulting 3-
chlorobenzo[b]selenophene 22 was obtained in a good yield of
72%. Replacing NaCl with NaBr and NaI resulted in the
formation
of
bromobenzo[b]selenophene
23
iodobenzo[b]selenophene 24 in the respective yields of 73% and
and
62%.
Acknowledgments
We also extended the scope of our chlorocyclization reaction
beyond aryl- and heteroaryl-containing enynes. The
We are grateful to Research Corporation for Science
Advancement for a Cottrell College Science Award (ID 23248),
the University of West Florida (UWF), and UWF’s Office of
Research and Sponsored Programs for supporting this research.
Research is also supported by the National Institute of General
Medical Sciences of the National Institutes of Health under grant
number 1T34GM110517-01. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health. Authors are
also grateful to Dr. Tim Royappa for his help and support
throughout the project.
chlorocyclization reaction of n-propyl enyne
7 and 1-
cyclohexenyl enyne 8 resulted in the formation of corresponding
3-chlorothiophenes 25 and 26 in the moderate yield of 64% and
55%, respectively (Scheme 4).
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mechanism of the cyclization reaction involving an I2 and Br2
electrophile is well established.26 Our method generates these
corrosive reagents in situ; thus, eliminating the potentially
harmful effects associated with the handling of these reagents.

5
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was added. To the mixture, sodium halide (5 equiv) and copper (II)
sulfate pentahydrate (5 equiv) were added. The reaction mixture was
allowed to stir at room temperature for 24 hours. All reaction mixtures
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Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 79.0,
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6
Tetrahedron
Highlights
First report on the synthesis of benzo[b]selenophene via chlorocyclization
“Table salt” is employed as the source of electrophilic chlorine
Green reaction using EtOH as solvent and non-corrosive sodium halides
Respective halogens (Cl, Br and I) can be incorporated by only changing sodium halide
Synthesis of halogenated oligothiophenes that are difficult to obtained otherwise