Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo- and 3,n-dihalobenzo[b]thiophenes

Article abstract of DOI:10.1016/j.tet.2018.04.080

A convenient methodology for the synthesis of mono- and di-halogenated benzo[b]thiophenes is described herein, which utilizes copper(II) sulfate pentahydrate and various sodium halides in the presence of substituted 2-alkynylthioanisoles. The proposed met

Full text of DOI:10.1016/j.tet.2018.04.080

Accepted Manuscript
Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo-
and 3,n-dihalobenzo[b]thiophenes
Tanay Kesharwani, Cory Kornman, Amanda Tonnaer, Amanda Hayes, Seoyoung
Kim, Nikesh Dahal, Ralf Romero, Andrew Royappa
PII:
S0040-4020(18)30485-X
10.1016/j.tet.2018.04.080
TET 29495
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 February 2018
Revised Date: 23 April 2018
Accepted Date: 24 April 2018
Please cite this article as: Kesharwani T, Kornman C, Tonnaer A, Hayes A, Kim S, Dahal N, Romero R,
Royappa A, Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo- and
3,n-dihalobenzo[b]thiophenes, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.080.
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Sodium halides as the source of electrophilic
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Tanay Kesharwani,a,* Cory Kornman,a Amanda Tonnaer,a Amanda Hayes,a Seoyoung Kim,b Nikesh Dahal,b
Ralf Romeroa and Andrew Royappaa
a Department of Chemistry, University of West Florida, Pensacola, FL 32514 USA
b Department of Chemistry, Bard College, Annandale-on-Hudson, NY 32514 USA

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Tetrahedron
journal homepage: www.elsevier.com
Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo-
and 3,n-dihalobenzo[b]thiophenes
Tanay Kesharwani,a,* Cory Kornman,a Amanda Tonnaer,a Amanda Hayes,a Seoyoung Kim,b Nikesh
Dahal,b Ralf Romeroa and Andrew Royappaa
a University of West Florida, Pensacola, FL 32514 USA
b Bard College, Annandale-on-Hudson, NY 32514 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient methodology for the synthesis of mono- and di-halogenated benzo[b]thiophenes is
described herein, which utilizes copper(II) sulfate pentahydrate and various sodium halides in
the presence of substituted 2-alkynylthioanisoles. The proposed method is facile, uses ethanol as
a green solvent, and results in uniquely substituted benzo[b]thiophene structures with isolated
yields up to 96%. The most useful component of this methodology is the selective introduction
of bromine atoms at every available position (2-7) around the benzo[b]thiophene ring, while
keeping position 3 occupied by a specific halogen atom such as Cl, Br or I. Aromatic halogens
are useful reactive handles; therefore, the selective introduction of halogens at specific positions
would be valuable in the targeted synthesis of bioactive molecules and complex organic
materials via metal-catalyzed cross coupling reactions. This work is a novel approach towards
the synthesis of dihalo substituted benzo[b]thiophene core structures, which provides a superior
alternative to the current methods discussed herein.
Available online
Keywords:
Benzo[b]thiophene
dihalobenzo[b]thiophene
Chlorocyclization
Bromocyclization
Iodocyclization
2009 Elsevier Ltd. All rights reserved
.
methods for the synthesis of the substituted core structures.12
Very recently, Reddy and Valetti developed [4+2]
1. Introduction
a
Substituted benzo[b]thiophenes and related chalcogen-
benzannulation between substituted alkenyl thiophenes and
various propargyl alcohols to furnish a diverse library of
benzo[b]thiophene derivatives13 with the substituents on the 5, 6,
and 7 positions. In another report, Yin et al. examined the direct
C-H arylation of benzo[b]thiophene using catalytic Pd(II) and
aryl chlorides to form 2-aryl benzo[b]thiophene derivatives.14 In
a similar report, Chen and coworkers utilized a Pd-catalyzed
coupling/cyclization reaction of 2-iodothiophenols with terminal
alkynes to achieve 2-aryl substituted benzo[b]thiophene
derivatives in moderate to high yields with fluoro-, chloro- and
trifluoromethyl-substituted 5 and 6 positions.15 Yamauchi and
coworkers introduced the multicomponent arylation/cyclization
containing
heterocycles,
such
as
benzofurans
and
benzoselenophenes, have received much attention in the recent
years due to their well-recognized biological1 and materials-
related applications.2 In particular, the molecules containing the
benzo[b]thiophene core structure have proven to be promising
candidates for biomedical applications, including 5-H7R and 5-
HTT receptor modulation, i.e., used in the treatment of
depression,3 estrogen receptor-alpha (ERα) and estrogen
receptor-beta (ERβ) modulation,4 breast cancer prevention,5
immune system regulation via S1P G-protein coupled receptors,6
and anti-malarial activity.7 Additional studies have shown that
uniquely substituted benzo[b]thiophenes may be useful in the
treatment of Staphylococcus infections.8 Organic materials
containing the benzothiophene core structure are showcased in
devices including novel phosphorescent organic light emitting
diodes (PHOLED’s) made possible by the low-lying LUMO and
high thermal stability associated with aromatic heterocycles;9
organic thin-film field effect transistors (OFET’s) dependent on
the high photostability and ionization potential of core-structure
organics;10 and dye-sensitized solar cells (DSSC’s).11
of
2-alkynylthioanisoles
to
furnish
2,3-diarylated
benzo[b]thiophene derivatives in
a
single step using
a
Pd/phenanthroline catalyst.16 Cyclization of arylketene
dithioacetal monoxides to afford 4, 5, and 6 methoxy-substituted
benzo[b]thiophenes was reported by Yoshida and coworkers.17 In
the recent literature, it is clear that necessity-driven syntheses
have been developed for the production of highly-substituted
benzo[b]thiophene structures and, when considered in
combination, the current methods provide a useful network of
strategies to afford variously functionalized structures at many
positions. However, to our knowledge, no single report has
defined a universal strategy for the selective placement of
halogens at any desired position on the benzo[b]thiophene ring.
Given the significant biological and materials applications
associated with benzo[b]thiophene derivatives, it is no surprise
that many synthetic chemists have worked to develop innovative

2
Tetrahedron
ACCEPTED MANUSCRIPT
Furthermore, no work to date has addressed the systematic
15 were synthesized with isolated yields between 89 and 98%
synthesis of dihalogenated benzo[b]thiophenes.
(Scheme 2).
Herein, we report a comprehensive method for the synthesis
of mono- and dihalogenated benzo[b]thiophenes via electrophilic
halocyclization of 2-alkynylthioanisoles. We have determined
previously that copper(II) sulfate pentahydrate and sodium halide
react in the presence of 2-alkynylthioanisoles 1 to afford mono-
halogenated benzo[b]thiophene derivatives 2 in isolated yields up
to 98% (Scheme 1).18 In this all-inclusive study, we have
expanded upon this foundation through the implementation of
new and varied functional groups to test the flexibility of this
reaction as well as to demonstrate a scaffold upon which
dihalogenated analogues may be achieved. The reaction of
bromo-substituted 2-akynylthioanisoles
3 under the same
reaction conditions gives dihalogenated benzo[b]thiophenes 4
with isolated yields up to 96% (Scheme 1).
Scheme 2
Using variously substituted 2-alkynylthioanisoles 6-15 as
starting materials, a diverse library of 3-halo benzo[b]thiophenes
16-45 were synthesized (Table 1). Beginning with a phenyl
substituent
benzo[b]thiophenes
(entries
1-3),
2-phenyl-3-halogenated
When 2-
were
synthesized.
alkynylthioanisole 6 was subjected to our cyclization conditions
using NaCl, 2-phenyl-3-chlorobenzo[b]thiophene 16 was formed
in excellent 92% yield. When alkyne 6 was subjected to similar
reaction conditions, where sodium bromide or iodide was
employed
bromobenzo[b]thiophene
instead
of
sodium
17
chloride,
and
2-phenyl-3-
2-phenyl-3-
iodobenzo[b]thiophene 18 were synthesized in 92% and 83%
yields respectively. When an alkyl chain was used instead of a
phenyl group on the remote alkyne group the corresponding 2-
alkynylthioanisoles, upon chlorocyclization, produced 2-n-buyl-
3-chlorobenzo[b]thiophene 19 in an excellent 86% yield. Once
again replacing NaCl with NaBr and NaI, but otherwise using the
same reaction conditions, resulted in the bromo- and
iodocyclized products 20 and 21 in 83% and 89% yields
respectively.
Scheme 1: Synthesis of 3-halobenzo[b]thiophenes and systematic synthesis
of 3-halo-n-bromobenzo[b]thiophene
Our approach works at room temperature, tolerates diverse
functionalities, and incorporates a green solvent. Additionally,
our reaction conditions are not only mild but also tolerant to
moisture and air. In addition, this method allows the placement of
a bromine reactive handle on positions 2, 4, 5, 6, and 7 around
the benzo[b]thiophene core ring, while placing chlorine, bromine,
or iodine moieties on position 3 depending on which sodium
halide (NaCl, NaBr, or NaI) is used for the synthesis. The
methods proposed in this report provide an array of easily
accessible halogenated compounds with a high potential for
functional diversity. The option to install halogens of choice
precisely at specific sites opens up many synthetic possibilities
due to the well-established halogen selectivity of metal-catalyzed
carbon-carbon coupling reactions (I > Br > Cl).
When a sterically hindered tert-butyl group was used in place
of the linear n-butyl group no significant change was observed in
reaction yield. The reaction worked equally well furnishing the
chloro cyclized product 22 in 82% yield as compared to the 86%
yield achieved with the n-butyl group (compare entries 22 and
19). Once again NaBr and NaI generated the desired cyclized 2-
tert-butyl-3-halobenzo[b]thiophenes 23 and 24 product in good
yields of 89% and 81% respectively. 2-Alkynylthioanisoles with
trimethylsilyl substituents (entries 10-12) underwent cyclization
to form 3-iodobenzo[b]thiophene 27 in excellent 91% yield;
however, attempts to synthesize chloro- and bromo- analogues 25
and 26 failed as the reaction yielded a complex, inseparable
mixture of products.
2. Results and Discussion
The desired 2-alkynylthioanisoles 6-15 used for the synthesis
of mono-halogenated benzo[b]thiophenes were prepared via
the Sonogashira coupling of 2-iodothioanisole 5 (1 equiv.)
with substituted terminal alkynes (1.2 equiv.) in the presence
of catalytic Pd (2 mol %) and catalytic copper (4 mol %)
using trimethylamine as solvent (Scheme 2).18,19 Using these
conditions, a variety of functionalized 2-akynylthioanisoles 6-
Our reaction tolerates vinyl groups as 2-(1-cyclohexen-1-
yl)thioanisole (entries 13-15) cyclized to form 3-
chlorobenzo[b]thiophene
28
in
82%
yield,
3-
bromobenzo[b]thiophene 29 in high yield of 98%, and 3-
iodobenzo[b]thiophene 30 in a yield of 81%. We also determined
that a primary alcohol works well in our cyclization reaction
conditions as the propargyl alcohol 11 (entries 16-18) cyclized in

the presence of NaCl to form
chlorobenzo[b]thiophene 31 in excellent 92% yield. Similarly,
alcohol 11 resulted in the formation of 3-
bromobenzo[b]thiophene 32 in 84% yield, and 3-
iodobenzo[b]thiophene 33 in 90% yield. Tertiary alcohol
substituents attached to the alkyne (entries 19-21) cyclized to
form the chloro- and bromo- substituted benzo[b]thiophene
analogues 34 and 35 in excellent 90% and 96% yields
respectively; however, the 2-iodo analogue 36 was formed in a
moderate yield of 75%.
desired 3-
functionality
resulted
in
the
formation
3-
tAheCCEPTED MANUSCRIPT
chlorobenzo[b]thiophene 37, 3-bromobenzo[b]thiophene 38, and
3-iodobenzo[b]thiophene 39 in isolated yields of 97%, 98%, and
97% respectively. Electron-rich alkyne 14 bearing a methoxy
group on the remote phenyl ring resulted in excellent yields of
98, 95 and 86% for 3-chlorobenzo[b]thiophene 40, 3-
bromobenzo[b]thiophene 41, and 3-iodobenzo[b]thiophene 42
respectively (entries 25-27). Hexynenitrile 15 (entries 28-30)
works equally well in our cyclization condition resulting in high
yields of the desired chloro, bromo and iodo products (43, 44 and
45), once again establishing the superiority of this methodology
both in terms of reaction yields and functional group tolerance
along with mild reaction conditions.
The ether functionality was tolerated well in our reaction
conditions as alkyne 13 (entries 22-24) bearing a methoxy
Table 1. Synthesis of 3-halobenzo[b]thiophenes using sodium halides as the source of electrophilic halogensa
Entry Substrate
Product
Lit. Yieldc,d
65d
Yieldb
92
Entry
16
Substrate
Product
Lit. Yieldc,d
Yieldb
92
1
2
3
6
6
6
16
17
18
11
31
32
33
-
92c
92
83
17
18
11
11
-
84
90
100c
86e
4
5
6
7
7
7
19
20
21
-
-
86
83
89
19
20
21
12
12
12
34
35
36
-
-
-
90
96
94
93e
7
8
9
8
8
8
22
23
24
87d
67c,10d
98c
82
89
81
22
23
24
13
13
13
37
38
39
-
-
97
98
97
97e
f
10
9
25
71d
-
25
14
40
71d
98
f
11
12
9
9
26
27
0c,57d
100c
-
26
27
14
14
41
42
87d
96c
95
86
91

4
Tetrahedron
ACCEPTED MANUSCRIPT
13
14
15
10
10
10
28
29
30
-
82
98
81
28
29
30
15
15
15
43
44
45
-
98
98
82
0c
79c
98c
97c
aReaction conditions: all reactions were performed using 0.30 mmol of thioether, 5.0 equiv of CuSO4•5H2O, and 5.0 equiv NaX (X = Cl, Br, I) in 5 mL of EtOH at room temperature
for 24 h.
bIsolated yield.
cLiterature yields reported by Larock and coworkers using I2 or Br2 as the electrophile.12m
dLiterature yields reported by Wu and coworkers using CuCl2 or CuBr2 as the electrophile.12n
eLiterature yields reported by our group using FeCl3 and NaI as the electrophile.19
fComplex reaction mixture.
Prior to this report the synthesis of 2-chlorobenzo[b]thiophenes
19, 28, 31, 34, 37 and 43 (entries 4, 13, 16, 19, 22 and 28) was
not established using electrophilic chlorocyclization. However,
the synthesis of 16, 22, 25 and 40 was reported by Wu and
coworkers12n by employing CuCl2 as the electrophile (entries 1,
7, 10 and 25). Our yields were either higher or comparable to
Wu’s yields for the products containing phenyl, 4-methoxy and
tert-butyl groups (entries 1, 7 and 25). Additionally, Wu’s
approach requires a higher temperature, toxic acetonitrile as the
solvent and a comparatively expensive copper salt making it less
desirable. Our only reaction which was inferior to Wu’s method
was the cyclization of trimethylsilyl substrate 9 as we could not
isolate the cyclized product 25 due to the formation of a complex
reaction mixture (entry 10).
employs the green solvent ethanol instead of the toxic and
carcinogenic solvent DCM. In addition, our methodology also
replaces corrosive iodine with relatively benign inorganic salts
such as NaI and CuSO4. The yields for the synthesis of 3-
iodobenzo[b]thiophenes 21, 33 and 39 (entries 6, 18, and 24)
were similar to our previously reported FeCl3/NaI iodocyclization
methodology.19
After establishing the synthesis of 3-halobenzo[b]thiophenes we
wanted to extend the scope of our cyclization methodology for
the systematic synthesis of n-bromo-3-dihalobenzo[b]thiophenes
(n = 2, 4, 5, 6, 7). To achieve this goal we began with developing
a strategy for the synthesis of o-(2-bromoethynyl)thioanisole 48,
a
substrate
halobenzo[b]thiophenes.
methylthiobenzaldehyde 46, when subjected to Corey-Fuchs
reaction conditions using carbon tetrabromide and
for
the
synthesis
Commercially-available
of
2-bromo-3-
2-
Our bromocyclization reaction was also superior to both Wu’s
and Larock’s bromocyclization involving Br2 and CuBr2 as the
electrophiles.12m The yield for the cyclization reaction involving
phenyl-substituted alkynylthioanisole 6 was identical for both our
method and Larock’s (entry 2). Interestingly, in exception to our
methodology, all other previously reported procedures failed to
produce a desired bromocyclized product in high yields when
alkyne 8 containing a tert-butyl group was employed for the
cyclization reaction (entry 8). Our method produced desired 2-
tert-butyl-3-bromobenzo[b]thiophene 23 in a high yield of 89%.
The poor yields reported by others were attributed to the
formation of an alkyne addition product. Likewise 2-(1-
cyclohexane-1-yl)thioanisole 10 resulted in the formation of 29
in 98% yield whereas Larock’s approach failed because of the
addition of Br2 to the remote vinyl group (entry 14). As observed
earlier with regard to chlorocyclization, our reaction was inferior
triphenylphosphine, produced dibromo alkene 47, which upon
elimination reaction conditions using DBU as a base afforded the
desired alkyne 48 in 78% overall yield for the two steps (Scheme
3).
Scheme 3
when trimethylsilyl substrate
9
was subjected to our
The substrate for the synthesis of 4-bromo-3-
halobenzo[b]thiophene derivatives was obtained via the selective
coupling of commercially-available 2,6-dibromo-iodobenzene 49
with trimethylsilyl acetylene using standard Sonogashira reaction
conditions to form the alkynyl-substituted 2,6-dibromobenzene
50 in 87% isolated yield. Subsequent reaction of alkynyl benzene
50 with n-butyllithium and dimethyl disulfide, followed by
deprotection with potassium carbonate in methanol, furnished the
terminal alkynyl thioanisole 51 in 60% isolated yield. In the final
step, the terminal alkyne 51 underwent Sonogashira coupling
with iodobenzene to afford the final substrate alkyne 52 with the
bromocyclization reaction conditions (entry 11). Bromoyclization
of alkyne 14 bearing a methoxy group and hexynenitrile 15 both
resulted in much higher yields with our reaction conditions when
compared with earlier reported approaches (entries 26 and 29). In
addition this is the first report of the synthesis of 2-
bromobenzo[b]thiophenes 20, 29, 32, 35 and 38 (entries 5, 14,
17, 20, and 23) by electrophilic bromocyclization.
Larock and coworkers reported that yields for the
iodocyclization reaction involving I2 as the electrophile were
higher than for our copper-mediated iodocyclization reaction
(entries 3, 9, 12, 15, 27 and 30). However, our methodology

desired bromine substitution in an isolated yield of 75% (Scheme
4).
Once the various brominated 2-alkynylthioanisoles were
generated via the syntheses outlined above (Schemes 3–7), a
variety of dihalogenated benzo[b]thiophenes were synthesized
using our reaction, with bromines placed at the 2, 3, 4, 5, 6, and 7
positions around the benzo[b]thiophene ring (Table 2). We began
ACCEPTED MANUSCRIPT
Br
I
Br
SiMe3
our
substrate
study
by
synthesizing
2-bromo-3-
PdCl2(PPh3)2
CuI, Et3N, r.t.
halobenzo[b]thiophene derivatives (entries 1-3). The three
dihalogenated benzo[b]thiophenes 62, 63 and 64 were obtained
from cyclization of o-(2-bromoethynyl)thioanisole 48 with NaCl,
NaBr and NaI in the presence of CuSO4•5H2O. 2-bromo-3-
iodobenzo[b]thiophene 64 resulted in 83% yield, whereas 2,3-
dibromobenzo[b]thiophene 63 resulted in 80% yield. Our
attempts to obtain 2-bromo-3-chlorobenzo[b]thiophene 62 in
synthetically useful yield failed as the product was only obtained
in 17% yield. To our surprise this reaction resulted in multiple
Br
Br
SiMe3
49
87% 50
1. n-BuLi, (MeS)2
2. K2CO3, MeOH
SMe
SMe
I
products
with
one
product
being
the
2,3-
PdCl2(PPh3)2
CuI, Et3N, r.t.
dichlorobenzo[b]thiophene analogue. We believe that the
formation of 2,3-dichlorobenzo[b]thiophene could be attributed
to a halogen exchange reaction of starting bromoalkyne 48 with
CuCl2 generated in situ via reaction of copper sulfate and sodium
halide. However, we did not find any precedent for any such
exchange reaction in the literature.
Br
Ph
Br
60% 51
75% 52
Scheme 4
To
obtain
5-bromobenzo[b]thiophene
and
6-
bromobenzo[b]thiophene, the analogous bromine-substituted
alkynes 57 and 58 were prepared via the reaction of
commercially-available 2-iodoanilines 53 and 54 with dimethyl
disulfide in the presence of tert-butyl nitrite to form the
thioanisole intermediates 55 and 56 with yields of 47% and 54%
respectively.20 Following this reaction, an iodine-selective
Sonogashira coupling was used to furnish the desired bromine-
substituted alkynyl substrates 57 and 58 resulting in isolated
yields of 88% and 91% respectively (Scheme 5).
4-bromo-3-halobenzo[b]thiophene derivatives (entries 4-6)
were made in 78% yield for the chloro-substituted analogue 65,
66% yield for the bromo-substituted analogue 66, and 64% yield
for the iodo-substituted analogue 67. The reaction yields were
slightly lower, as expected due to steric hindrance from the
nearby bromine group interfering with the approach of the
electrophile to the alkyne in the cyclization step. This theory was
verified by the expected trend of atomic size of the approaching
electrophile. The chlorocyclization product was obtained in
higher yield as compared to the bromocyclization product, which
in turn was obtained in higher yield than the iodocyclization
product.
4- and 5-bromo-3-halobenzo[b]thiophenes (entries 7-12) were
synthesized in high yields. Starting alkynes 57 and 58, when
cyclized using NaCl and CuSO4, resulted in identical yields of
89% for both the cyclized products 68 and 71. In molecules 57
and 58, the bromine atoms at both the 4- and 5- positions are too
remote to exert a steric effect on the cyclization. The reaction
yields were higher and comparable (compare entries 8 and 11;
and entries 9 and 12). Therefore it also seems that the electron
withdrawing bromine does not have an effect on the cyclization
reaction.
Therefore,
7-bromo-3-halobenzo[b]thiophene
Scheme 5
derivatives (entries 13-15) were realized in good to excellent
yields. Chlorocyclization of alkyne 61 to 7-bromo-3-
chlorobenzo[b]thiophene 74 resulted in a moderate 73% yield. To
our surprise bromo- and iodocyclization of 61 resulted in much
higher yields of 92% for 3,7-dibromobenzo[b]thiophene 75 and
91% for 7-bromo-3-iodobenzo[b]thiophene 76.
The starting material used for the synthesis of 7-bromo-3-
halobenzo[b]thiophenes was obtained via selective lithiation of
commercially available m-bromoiodobenzene (59) using lithium
diisopropylamide (LDA) followed by the addition of methyl
disulfide in anhydrous THF as the solvent.21 The resulting di-
halogenated thioanisole derivative 60 was obtained in 66%
isolated yield. The previous reaction was followed by an iodine-
selective Sonogashira coupling with phenylacetylene for the
production of 6-bromo-2-alkynylthioanisole 61 with an isolated
yield of 77% (Scheme 6).
Table 1. Synthesis of 3-halobenzo[b]thiophenes using sodium
halides as the source of electrophilic halogensa
Entry
1
Substrate
Product
Yieldb
17c
48
62
Scheme 6

6
Tetrahedron
we believe that the iodocyclization proceeds through the well-
ACCEPTED MANUSCRIPT
established mechanism involving I2 as the electrophile.22
2
48
63
80
CuSO4·5H2O, when mixed with NaCl in ethanol, results in the
formation of CuCl2 which is known to rapidly equilibrate
between species such as [CuCl]+, [CuCl3]-, and [CuCl4]2-.23 We
believe that one or more of these electrophilic species are
responsible for the reported efficient and high-yielding
chlorocyclization reactions. Copper(II) sulfate pentahydrate in
ethanol remains as an insoluble blue solid, but upon addition of
NaCl to the mixture, the solution changes to a yellow-green color
indicative of dissolution and complex ion formation. A similar
color change was observed in the reported chlorocyclization
reactions. In an analogous reaction CuSO4 and NaBr also results
in the formation of CuBr2. In theory, CuCl2 and CuBr2 could
decompose to form Cl2 and Br2. However, it is well established
that the CuCl2 decomposes to CuCl and Cl2 only at 1000 °C.
Therefore cyclization reactions involving Cl2 as the electrophile
are less likely and we believe that the above ionic species are
likely to act as the electrophile in these cyclization reactions.
3
4
48
52
64
65
83
78
5
6
52
52
66
67
66
64
Decomposition of CuBr2 into CuBr and Br2 occurs at a lower
temperature. Therefore, cyclization involving Br2 is very likely.
However, if Br2 is involved, it would also be more likely to result
in the formation of side products involving electrophilic aromatic
substitution reactions especially with the electron-rich substrates
such as alkyne 14 (Table 1, entry 26). To our surprise, we did not
observe any aromatic halogenation as the side products in any of
the bromocyclization reactions. In addition, alkyne 10, which
contains a vinyl functionality, did not show any Br2 addition to
the vinyl group, suggesting the absence of Br2 in the reaction
mixture.
7
57
68
89
8
9
57
57
69
70
91
94
10
58
71
89
11
12
58
58
72
73
86
96
Scheme 7
13
14
15
61
61
61
74
75
76
73
92
91
In order to confirm our theory, we subjected the electron-rich
anisole to electrophilic bromination in ethanol using Br2 and
CuSO4/NaBr as the electrophiles (Scheme 7). Addition of Br2
resulted in the formation of 4-bromoanisole in 85% yield,
whereas our reaction conditions involving CuSO4/NaBr failed to
generate any 4-bromoanisole even after 48 hrs. Therefore we
believe that CuBr2 is the electrophilic reagent initiating the
cyclization reaction and not Br2.
The proposed mechanism of the chlorocyclization and
bromocyclization reactions are outlined in Scheme 8. Cu(II) can
coordinate with the alkyne 1 followed by an anti-attack from a
nearby S nucleophile to give the cationic intermediate 77. The
methyl group can be removed subsequently by SN2 displacement
with the help of CuX2 (X = Cl or Br), eventually forming the
desired cyclized product 79.
aReaction conditions A: all reactions were performed using 0.30 mmol of thioether, 5.0
equiv of CuSO4•5H2O, and 5.0 equiv NaX (X = Cl, Br, I) in 5 mL of EtOH at room
temperature for 24 h. Reaction conditions
bIsolated yield.
cNMR yield.
Copper sulfate is the most common, non-toxic and
inexpensive copper(II) reagent. CuSO4, when mixed with NaI, is
known to form CuI2 which decomposes readily into CuI and I2.
When iodocyclization reactions were analyzed via TLC, we
observed the formation of a purple spot indicative of the
formation of molecular iodine in the reaction mixture. Therefore

(m, 1H), 7.81-7.84 (m, 1H). Other characterization data are in
ACCEPTED MANUSCRIPT
good agreement with the previous reported data.12m
2-n-Butyl-3-Chlorobenzo[b]thiophene (19). Product was
1
isolated as a colorless oil; H NMR (400 MHz, chloroform-d) δ
0.97 (t, J = 7.6 Hz, 3H), 1.40-1.49 (m, 2H), 1.68-1.76 (m, 2H),
2.95 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.2
Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
chloroform-d) δ 13.9, 22.4, 28.2, 32.6, 117.4, 121.5, 122.5,
124.7, 124.8, 136.5, 137.2, 139.2; IR (neat) 3063.3, 2957.2,
2928.5, 2871.4, 2858.8, 1564.7, 1537.9, 1457.6, 1435.9, 1378.7,
1310.9, 1253.8, 1068.8, 1018.4, 941.3. HRMS (EI+, m/z) calcd
for (C12H13ClS)+ 224.0427, found 224.0431.
Scheme 8
2-n-Butyl-3-Bromobenzo[b]thiophene (20). Product was
isolated as a pale yellow oil; H NMR (400 MHz, chloroform-d)
1
3. Conclusion
δ 0.97 (t, J = 7.6 Hz, 3H), 1.41-1.50 (m, 2H), 1.69-1.77 (m, 2H),
2.96 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6
Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H). Other characterization data are
in good agreement with the previous reported data.24
A convenient method is introduced for the synthesis of mono-
halogenated and di-halogenated benzo[b]thiophene derivatives
via electrophilic cyclization of 2-alkynylthioanisoles. This
method allows selective placement of bromine atoms upon every
available position on the benzo[b]thiophene ring, i.e., the 2, 3, 4,
5, 6, and 7 positions. The 3 position may be interchanged with
iodine or chlorine moieties depending on which sodium halide is
used during synthesis. We believe this method stands out among
the previously established methods as a new and innovative
alternative towards the synthesis of highly functionalized
benzo[b]thiophene derivatives.
2-n-Butyl-3-Iodobenzo[b]thiophene (21). Product was isolated
as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ 0.98 (t, J =
7.2 Hz, 3H) 1.40-1.53 (m, 2H) 1.69-1.78 (m, 2H) 2.97 (t, J = 7.6
Hz, 2H) 7.31 (t, J = 7.6 Hz, 1H) 7.41 (t, J = 8.0 Hz, 1H) 7.70 (d,
J = 8.4 Hz, 1H) 7.72 (d, J = 8.0 Hz, 1H). Other characterization
data are in good agreement with the previous reported data.19
2-tert-butyl -3-Chlorobenzo[b]thiophene (22). Product was
1
isolated as a yellow oil; H NMR (400 MHz, chloroform-d) δ
4. Experimental section
1.56 (s, 9H), 7.33 (td, J = 8.0, 1.2 Hz, 1H), 7.41 (td, J = 7.2, 1.2
Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H). Other
characterization data are in good agreement with the previous
reported data.12n
Solvents and other starting chemicals were obtained from
commercial suppliers and used without any further purification.
1H and 13C NMR spectra were recorded on a Bruker spectrometer
at 400 and 100 MHz, respectively. High-resolution mass spectra
(HRMS) were recorded on a VG-70S magnetic sector mass
spectrometer using direct probe sample introduction and electron
ionization (EI). Reaction progress was monitored using thin layer
3-Bromo-2-tert-butylbenzo[b]thiophene (23). Product was
1
isolated as a yellow oil; H NMR (400 MHz, chloroform-d) δ
1.59 (s, 9H), 7.33 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H),
7.73 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H). Other
characterization data are in good agreement with the previous
reported data.12m
chromatography on glass plates coated with silica gel 60 F254
.
Short wave UV light was used to visualize the aromatic
molecules. Flash column chromatography was performed using
silica gel (60−120 mesh) with ACS grade solvents. The alkynes
6-15 and thioanisole 60 were prepared according to literature
procedures.19,21
2-tert-butyl-3-Iodobenzo[b]thiophene (24).
Product was
1
isolated as a yellow oil; H NMR (400 MHz, chloroform-d) δ
1.63 (s, 9H), 7.32 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H),
7.72 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H). Other
characterization data are in good agreement with the previous
reported data.19
General procedure for the synthesis of compounds 16-24,
27-45 and 62-76.
To a vial containing 2-alkynylthioanisole (0.3 mmol) in 5 mL
of EtOH was added desired sodium halide (1.5 mmol) and
CuSO4•5H2O (1.5 mmol). The reaction mixture was allowed to
stir overnight. The reaction mixture was filtered and absorbed in
silica gel before purification via column chromatography using
hexanes and ethyl acetate as eluent.
3-Iodo-2-(trimethylsilyl)benzo[b]thiophene (27). Product was
isolated as a pale yellow oil; H NMR (400 MHz, chloroform-d)
δ 0.51 (s, 9H), 7.37 (td, J = 8.0, 1.2 Hz, 1H), 7.44 (td, J = 7.2, 1.2
Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H). Other
characterization data are in good agreement with the previous
reported data.12m
1
3-Chloro-2-phenylbenzo[b]thiophene (16).
Product was
3-Chloro 2-(cyclohex-1-enyl)benzo[b]thiophene (28). Product
o
1
o
1
isolated as a white solid, mp 64-67 C; H NMR (400 MHz,
chloroform-d) δ 7.39-7.51 (m, 5H), 7.79-7.87 (m, 3H), 7.88 (d, J
= 7.2 Hz, 1H). Other characterization data are in good agreement
with the previous reported data.12n
was isolated as an off-white solid: mp 39-41 C; H NMR (400
MHz, chloroform-d) δ 1.69-1.72 (m, 2H), 1.79-1.81 (m, 2H),
2.27 (m, 2H), 2.54 (m, 2H), 6.37 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H),
7.41 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0
Hz, 1H); 13C NMR (100 MHz, chloroform-d) δ 21.9, 23.0, 26.0,
29.3, 115.2, 121.9, 122.3, 124.9, 125.1, 130.3, 131.8, 136.0,
138.0, 139.4; IR (neat) 2933.5, 1639.4, 1559.2, 1435.0, 1320.8,
1252.2, 1137.9, 1073.0, 1018.4, 948.7, 888.7, 832.8, 787.2,
752.5, 727.6, 700.6. HRMS (EI+, m/z) calcd for (C14H13ClS)+
248.0427, found 248.0426.
3-Bromo-2-phenylbenzo[b]thiophene (17).
Product was
o
1
isolated as a white solid, mp 62-64 C; H NMR (400 MHz,
chloroform-d) δ 7.39-7.51 (m, 5H), 7.76-7.78 (m, 2H), 7.81 (d, J
= 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H). Other characterization
data are in good agreement with the previous reported data.12m
3-Iodo-2-phenylbenzo[b]thiophene (18). Product was isolated
as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ 7.37 (td, J =
7.5, 1.5 Hz, 1H), 7.42-7.50 (m, 4H), 7.66-7.69 (m, 2H), 7.75-7.78
3-Bromo-2-(cyclohex-1-enyl)benzo[b]thiophene (29). Product
1
was isolated as a colorless oil; H NMR (400 MHz, chloroform-

8
Tetrahedron
ACCEPTED MANUSCRIPT
d) δ 1.70-1.72 (m, 2H), 1.79-1.83 (m, 2H), 2.26 (m, 2H), 2.52
Hz, 1H); 13C NMR (100 MHz, chloroform-d) δ 21.9, 25.2, 36.8,
(m, 2H), 6.32 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz,
1H), 7.73 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H). Other
characterization data are in good agreement with the previous
reported data.12m
73.5, 74.3, 122.2, 125.2, 125.3, 125.5, 137.0, 142.8, 152.0; IR
(neat) 3397.4, 2933.2, 2858.9, 1639.0, 1556.3, 1450.4, 1433.3,
1384.4, 1242.8, 1219.7, 1150.1, 1063.0, 1019.9, 964.7, 904.9,
811.6, 770.3, 751.3, 727.8, 616.8. HRMS (EI+, m/z) calcd for
(C14H15IOS)+ 357.9888, found 357.9897.
2-(Cyclohex-1-enyl)-3-idobenzo[b]thiophene (30).
Product
was isolated as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ
1.68 – 1.76 (m, 2H), 1.77 – 1.85 (m, 2H), 2.22 – 2.30 (m, 2H),
2.42-2.50 (m, 2H), 6.16-6.21 (m, 1H), 7.32 (td, J = 8.2, 1.2 Hz,
1H), 7.41 (td, J = 8.0, 1.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.74
(d, J = 8.0 Hz, 1H). Other characterization data are in good
agreement with the previous reported data.19
(3-chloro-1-benzothiophen-2-yl)methyl methyl ether (37).
Product was isolated as a yellow oil; 1H NMR (400 MHz,
chloroform-d) δ 3.45 (s, 3H), 4.78 (s, 2H), 7.39 (t, J = 7.2 Hz,
1H), 7.44 (t, J = 7.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, chloroform-d) δ 58.5, 67.4, 119.0, 122.0, 122.8,
125.0, 125.6, 135.0, 136.7, 137.6; IR (neat) 3060.68, 2989.0,
2927.3, 2822.2, 1727.3, 1672.0, 1510.4, 1435.2, 1368.4, 1312.1,
1254.4, 1234.9, 1094.9, 1020.9, 941.6, 753.7, 727.7. HRMS
(EI+, m/z) calcd for (C10H9ClOS)+ 212.0063, found 212.0061.
(3-Chloro-1-benzothiophen-2-yl)methanol (31). Product was
o
1
isolated as a white solid: mp 91-92 C; H NMR (400 MHz,
chloroform-d) δ 2.02 (s, 1H), 4.98 (d, J = 4.0 Hz, 2H), 7.39 (t, J =
7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H);
13C NMR (100 MHz, chloroform-d) δ 58.6, 118.0, 122.0, 122.9,
125.1, 125.7, 136.9, 137.3, 137.4; IR (neat) 2928.3, 2851.0,
1627.5, 1561.4, 1456.9, 1219.7, 1014.0, 984.5, 771.9, 757.4,
728.9. HRMS (EI+, m/z) calcd for (C9H7ClOS)+ 197.9906, found
197.9906.
(3-bromo-1-benzothiophen-2-yl)methyl methyl ether (38).
Product was isolated as a yellow oil; 1H NMR (400 MHz,
chloroform-d) δ 3.46 (s, 3H), 4.78 (s, 2H), 7.38 (t, J = 8.0 Hz,
1H), 7.44 (t, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.80 (d, J
= 7.6 Hz, 1H); 13C NMR (100 MHz, chloroform-d) δ 58.6, 69.0,
106.8, 122.7, 123.2, 125.2, 125.6, 125.8, 137.1, 138.2; IR (neat)
3059.1, 2988.3, 2926.8, 2821.4, 1728.3, 1671.2, 1504.6, 1456.1,
1434.5, 1366.1, 1304.8, 1251.1, 1193.7, 1096.1, 1020.3, 920.2,
753.0, 726.7. HRMS (EI+, m/z) calcd for (C10H9BrOS)+
255.9557, found 255.9564.
(3-bromo-1-benzothiophen-2-yl)methanol (32). Product was
o
1
isolated as a white solid: mp 92-94 C; H NMR (400 MHz,
chloroform-d) δ 2.00 (bs, 1H), 4.99 (d, J = 6.0 Hz, 2H), 7.39 (t, J
= 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 2H);
13C NMR (100 MHz, chloroform-d) δ 60.1, 105.8, 122.8, 123.1,
125.3, 125.6, 137.9, 138.3, 139.3; IR (neat) 2927.5, 2855.0,
1627.6, 1560.0, 1455.3, 1336.1, 1219.9, 1127.0, 1010.1, 772.2,
757.0, 681.7. HRMS (EI+, m/z) calcd for (C9H7BrOS)+
241.9401, found 241.9407.
(3-iodo-1-benzothiophen-2-yl)methyl methyl ether (39).
Product was obtained as a yellow liquid; H NMR (400 MHz,
chloroform-d) δ 3.47(s, 3H), 4.77 (s, 2H), 7.37 (td, J = 7.2, 1.2
Hz, 1H), 7.43 (td, J = 7.2, 1.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H),
7.78 (d, J = 8.0 Hz, 1H). Other characterization data are in good
agreement with the previous reported data.19
1
(3-iodo-1-benzothiophen-2-yl)methanol (33). The product was
o
1
obtained as a white solid, mp 97-99 C; H NMR (400 MHz,
chloroform-d) δ 2.05 (s, 1H), 4.97 (d, J = 5.8 Hz, 2H), 7.37 (t, J =
7.8 Hz, 1H), 7.43 (t, J = 6.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H),
7.78 (d, J = 8.2 Hz, 1H). Other characterization data are in good
agreement with the previous reported data.19
4-(3-chloro-1-benzothiophen-2-yl)phenyl methyl ether (40).
o
1
Product was isolated as an off-white solid: mp 100-101 C; H
NMR (400 MHz, chloroform-d) δ 3.87 (s, 3H), 7.01 (d, J = 8.4
Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.73
(d, J = 8.8 Hz, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz,
1H). Other characterization data are in good agreement with the
previous reported data.12n
1-(3-chlorobenzothiophen-2-yl)cyclohexanol (34). Product was
o
1
isolated as a white solid: mp 50-53 C; H NMR (400 MHz,
chloroform-d) δ 1.32-1.42 (m, 1H), 1.71-1.79 (m, 5H), 1.90-2.00
(m, 2H), 2.28-2.36 (m, 2H), 2.43 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H),
7.42 (t, J = 7.6 Hz, 1H), 7.76-7.79 (m, 2H); 13C NMR (100 MHz,
chloroform-d) δ 21.8, 25.3, 36.4, 73.8, 113.7, 121.5, 122.5,
124.9, 125.0, 135.6, 138.6, 147.4; IR (neat) 3379.7, 2935.8,
2854.0, 1628.1, 1560.2, 1448.2, 1381.0, 1306.7, 1250.4, 1219.7,
1154.9, 1062.7, 1034.8, 1019.0, 966.0, 933.0, 906.6, 870.8,
828.7, 772.2, 755.3, 730.2. HRMS (EI+, m/z) calcd for
(C14H15ClOS)+ 266.0532, found 266.0538.
4-(3-bromo-1-benzothiophen-2-yl)phenyl methyl ether (41).
o
1
Product was isolated as an off-white solid: mp 86-88 C; H
NMR (400 MHz, chloroform-d) δ 3.87 (s, 3H), 7.01 (d, J = 8.4
Hz, 2H), 7.38 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.71
(d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz,
1H). Other characterization data are in good agreement with the
previous reported data.12n,25
4-(3-iodo-1-benzothiophen-2-yl)phenyl methyl ether (42).
o
1
Product was obtained as a white solid, mp 84-86 C; H NMR
(400 MHz, chloroform-d) δ 3.80 (s, 3H), 6.95 (d, J = 8.6 Hz,
2H), 7.32 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.59 (d, J =
8.7 Hz, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H).
Other characterization data are in good agreement with the
previous reported data.26
1-(3-bromobenzothiophen-2-yl)cyclohexanol (35). Product was
o
1
isolated as a white solid: mp 79-81 C; H NMR (400 MHz,
chloroform-d) δ 1.32-1.42 (m, 1H), 1.73-1.79 (m, 5H), 1.90-2.00
(m, 2H), 2.34-2.42 (m, 2H), 2.48 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H),
7.43 (t, J = 7.2 Hz, 1H), 7.78 (t, J = 8.0 Hz, 2H); 13C NMR (100
MHz, chloroform-d) δ 21.8, 25.2, 36.5, 74.1, 101.1, 122.3, 122.8,
125.0, 125.1, 136.3, 139.9, 149.0; IR (neat) 2932.9, 1627.3,
1557.8, 1452.7, 1380.9, 1335.5, 1219.8, 1063.9, 965.1, 818.7,
772.3, 729.1, 675.0. HRMS (EI+, m/z) calcd for (C14H15BrOS)+
310.0027, found 310.0019.
4-(3-Chlorobenzo[b]thiophene-2-yl)butanenitrile (43). Product
1
was isolated as a colorless oil; H NMR (400 MHz, chloroform-
d) δ 2.08-2.15 (m, 2H), 2.43 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2
Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.76
(d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, chloroform-d) δ 16.6, 26.2, 27.1, 118.9, 119.1, 121.8,
122.6, 125.2, 125.4, 135.4, 136.6, 137.0; IR (neat) 3061.5,
2931.5, 2248.1, 1565.0, 1538.0, 1432.1, 1313.6, 1254.2, 1160.5,
1068.1, 1017.7, 941.1, 752.8, 727.0, 667.5. HRMS (EI+, m/z)
calcd for (C12H10ClNS)+ 235.0222, found 235.0220.
1-(3-iodobenzothiophen-2-yl)cyclohexanol (36). Product was
o
1
isolated as an off-white solid: mp 117-119 C; H NMR (400
MHz, chloroform-d) δ 1.35-1.45 (m, 1H), 1.75-1.85 (m, 5H),
1.90-2.00 (m, 2H), 2.39-2.46 (m, 3H), 7.34 (t, J = 8.0 Hz, 1H),
7.42 (t, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.4

4-(3-Bromobenzo[b]thiophene-2-yl)butanenitrile (44). Product
was isolated as a colorless oil; H NMR (400 MHz, chloroform-
752.9, 735.8, 690.7. HRMS (EI+, m/z) calcd for (C14H8ClIS)+
321.9219, found 321.9216.
ACCEPTED MANUSCRIPT
1
d) δ 2.09-2.16 (m, 2H), 2.44 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.2
Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.76
(d, J = 8.0 Hz, 2H). Other characterization data are in good
agreement with the previous reported data.12m
3,5-dibromo-2-phenyl-benzothiophene (69). Product was
o
1
isolated as a white solid: mp 131-133 C; H NMR (400 MHz,
chloroform-d) δ 7.42-7.51 (m, 4H), 7.68 (d, J = 8.8 Hz, 1H), 7.75
(d, J = 7.2 Hz, 2H), 8.02 (s, 1H); 13C NMR (100 MHz,
chloroform-d) δ 104.0, 119.5, 123.6, 126.5, 128.7, 128.8, 129.2,
129.7, 132.7, 136.4, 140.2, 140.9; IR (neat) 1578.6, 1485.8,
1435.9, 1260.5, 1071.6, 1059.8, 977.9, 902.9, 808.0, 795.7,
750.1. HRMS (EI+, m/z) calcd for (C14H8Br2S)+ 365.8713, found
365.8712.
4-(3-Iodobenzo[b]thiophene-2-yl)butanenitrile (45). Product
was isolated as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ
2.07-2.17 (m, 2H), 2.44 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.2 Hz,
2H), 7.35 (td, J = 8.2, 1.2 Hz, 1H), 7.42 (td, J = 8.0, 1.2 Hz, 1H),
7.70 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H). Other
characterization data are in good agreement with the previous
reported data.19
5-bromo-3-iodo-2-phenyl-benzothiophene (70). Product was
o
1
isolated as a white solid: mp 117-119 C; H NMR (400 MHz,
chloroform-d) δ 7.46-7.50 (m, 4H), 7.64-7.68 (m, 3H), 7.99 (s,
1H); 13C NMR (100 MHz, chloroform-d) δ 78.2, 119.7, 123.6,
128.7, 128.7, 129.2, 129.3, 130.1, 134.3, 137.8, 143.8, 144.2; IR
(neat) 1432.1, 1219.8, 1070.6, 970.1, 896.9, 860.2, 787.5, 772.5,
751.6, 727.5, 694.4. HRMS (EI+, m/z) calcd for (C14H8BrIS)+
413.8575, found 413.8562.
2,3-dibromobenzothiophene (63). Product was isolated as a
colorless oil; 1H NMR (400 MHz, chloroform-d) δ 7.38 (t, J = 6.4
Hz, 1H), 7.43 (t, J = 6.4 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.75
(d, J = 8.0 Hz, 1H). Other characterization data are in good
agreement with the previous reported data.12m,27
2-bromo-3-iodo-benzothiophene (64). Product was isolated as a
colorless oil; 1H NMR (400 MHz, chloroform-d) δ 7.37 (t, J = 8.0
Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.65-7.71 (m, 2H); 13C NMR
(100 MHz, chloroform-d) δ 87.3, 119.8, 122.1, 126.0, 126.1,
126.4, 140.5, 141.2. IR (neat) 2926.9, 1485.7, 1451.6, 1425.4,
1416.7, 1243.3, 1219.8, 1019.7, 980.9, 882.9, 772.5, 748.5,
720.9, 706.7. HRMS (EI+, m/z) calcd for (C8H4BrIS)+ 337.8262,
found 337.8269.
6-bromo-3-chloro-2-phenyl-benzothiophene (71). Product was
o
1
isolated as a white solid: mp 120-122 C; H NMR (400 MHz,
chloroform-d) δ 7.41 -7.52 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H),
7.72 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.2 Hz, 2H), 7.96 (s, 1H);
13C NMR (100 MHz, chloroform-d) δ 116.6, 119.6, 123.6, 124.9,
128.7, 128.9, 129.1, 129.3, 132.0, 136.9, 137.0, 138.2; IR (neat)
2927.0, 1585.5, 1556.4, 1486.3, 1449.9, 1385.7, 1317.1, 1220.0,
1089.5, 1052.2, 898.4, 851.8, 799.9, 772.2, 762.2, 688.5. HRMS
(EI+, m/z) calcd for (C14H8BrClS)+ 321.9219, found 321.9219.
4-bromo-3-chloro-2-phenyl-benzothiophene (65). Product was
o
1
isolated as a white solid: mp 90-92 C; H NMR (400 MHz,
chloroform-d) δ 7.20 (t, J = 8.0 Hz, 1H), 7.42-7.51 (m, 3H), 7.66-
7.71 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
chloroform-d) δ 116.6, 117.3, 122.1, 125.8, 128.8, 129.1, 129.9,
131.6, 132.4, 133.4, 139.0, 139.6; IR (neat) 3055.2, 2926.7,
2854.5, 1543.1, 1483.2, 1446.0, 1397.6, 1310.9, 1187.2, 1093.2,
906.8, 771.4, 749.9, 726.7, 693.9. HRMS (EI+, m/z) calcd for
(C14H8BrClS)+ 321.9219, found 321.9212.
3,6-dibromo-2-phenyl-benzothiophene (72). Product was
o
1
isolated as a white solid: mp 125-127 C; H NMR (400 MHz,
chloroform-d) δ 7.41-7.52 (m, 3H), 7.57 (d, J = 8.4 Hz, 1H),
7.70-7.76 (m, 3H), 7.96 (s, 1H); 13C NMR (100 MHz,
chloroform-d) δ 104.8, 119.6, 124.8, 125.0, 128.8, 128.9, 129.2,
129.7, 132.8, 138.2, 139.0, 139.1; IR (neat) 2926.6, 1584.3,
1550.9, 1484.7, 1446.4, 1384.9, 1296.4, 1219.8, 1088.3, 1052.0,
888.1, 798.3, 772.3, 759.2, 740.9, 688.1. HRMS (EI+, m/z) calcd
for (C14H8Br2S)+ 365.8713, found 365.8717.
4-bromo-3-bromo-2-phenyl-benzothiophene (66). Product was
o
1
isolated as a white solid: mp 111-114 C; H NMR (400 MHz,
chloroform-d) δ 7.20 (t, J = 7.6 Hz, 1H), 7.45-7.50 (m, 3H), 7.65
(d, J = 6.4 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz,
1H), 7.80 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, chloroform-
d) δ 104.4, 117.2, 122.0, 122.2, 123.7, 125.2, 125.5, 128.5, 128.6,
128.8, 129.0, 129.7, 130.2, 131.7, 133.4, 133.9, 140.2, 140.9; IR
(neat) 3020.6, 2926.2, 2854.5, 1539.8, 1475.8, 1444.9, 1395.1,
1257.8, 1185.1, 1090.1, 890.7, 803.2, 760.7, 747.4, 725.3, 695.4.
HRMS (EI+, m/z) calcd for (C14H8Br2S)+ 365.8713, found
365.8716.
6-bromo-3-iodo-2-phenyl-benzothiophene (73). Product was
o
1
isolated as a yellow solid: mp 115-116 C; H NMR (400 MHz,
chloroform-d) δ 7.46-7.52 (m, 3H), 7.56 (d, J = 8.4 Hz, 1H), 7.68
(d, J = 8.0 Hz, 3H), 7.94 (s, 1H); 13C NMR (100 MHz,
chloroform-d) δ 78.9, 119.6, 124.6, 127.5, 128.7, 129.0, 129.3,
130.1, 134.3, 140.2, 141.0, 142.9; IR (neat) 2926.3, 1443.4,
1384.2, 1219.7, 1088.1, 872.5, 852.9, 797.7, 772.3, 735.6, 693.7.
HRMS (EI+, m/z) calcd for (C14H8BrIS)+ 413.8575, found
413.8583.
4-bromo-3-iodo-2-phenyl-benzothiophene (67). Product was
7-bromo-3-chloro-2-phenyl-benzothiophene (74). Product was
o
1
o
1
isolated as a white solid: mp 131-134 C; H NMR (400 MHz,
chloroform-d) δ 7.19 (t, J = 8.0 Hz; 1H), 7.47-7.49 (m, 3H), 7.53-
7.55 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H);
13C NMR (100 MHz, chloroform-d) δ 118.4, 122.3, 125.3, 128.6,
129.3, 130.2, 130.7, 131.8, 135.3, 135.9, 141.3, 145.5; IR (neat)
2925.8, 2854.5, 1537.6, 1471.8, 1434.6, 1394.1, 1181.6, 1091.0,
878.2, 794.4, 761.6, 741.4, 722.2, 693.8. HRMS (EI+, m/z) calcd
for (C14H8BrIS)+ 413.8575, found 413.8587.
isolated as a white solid: mp 87-89 C; H NMR (400 MHz,
chloroform-d) δ 7.36 (t, J = 7.6 Hz, 1H), 7.45-7.50 (m, 3H), 7.56
(d, J = 7.6 Hz, 1H), 7.82 (t, J = 8.8 Hz, 3H); 13C NMR (100
MHz, chloroform-d) δ 115.7, 117.2, 121.3, 126.4, 128.2, 128.8,
129.0, 129.3, 131.9, 137.8, 138.4, 138.9; IR (neat) 3685.2,
3620.9, 3020.0, 2977.5, 2400.6, 1522.1, 1477.3, 1423.7, 1215.4,
1046.7, 929.0, 771.1, 669.4. HRMS (EI+, m/z) calcd for
(C14H8BrClS)+ 321.9219, found 321.9217.
5-bromo-3-chloro-2-phenyl-benzothiophene (68). Product was
3,7-dibromo-2-phenyl-benzothiophene (75). Product was
o
1
o
1
isolated as a white solid: mp 118-119 C; H NMR (400 MHz,
chloroform-d) δ 7.43-7.49 (m, 4H), 7.67 (d, J = 8.4 Hz, 1H), 7.78
(d, J = 8.0 Hz, 2H), 8.02 (s, 1H); 13C NMR (100 MHz,
chloroform-d) δ 115.9, 119.4, 123.8, 125.1, 128.7, 128.9, 129.2,
129.4, 132.0, 135.5, 138.3, 139.6; IR (neat) 1581.5, 1486.0,
1437.1, 1264.5, 1220.0, 1058.4, 993.6, 796.5, 772.4, 735.8,
isolated as a white solid: mp 77-78 C; H NMR (400 MHz,
chloroform-d) δ 7.36 (t, J = 8.0 Hz, 1H), 7.43-7.52 (m, 3H), 7.56
(d, J = 7.6 Hz, 1H), 7.78 (d, J = 6.8 Hz, 2H), 7.83 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, chloroform-d) δ 105.4, 115.5, 122.7,
126.5, 128.1, 128.7, 129.1, 129.6, 132.6, 139.3, 139.7, 140.1; IR
(neat) 3686.2, 3617.6, 3020.0, 2400.6, 1524.1, 1478.5, 1423.9,

10
Tetrahedron
ACCEPTED MANUSCRIPT
1393.4, 1215.6, 1047.3, 929.0, 770.8, 669.4, 627.1. HRMS
added dropwise to the mixture. The reaction mixture was allowed
(EI+, m/z) calcd for (C14H8Br2S)+ 365.8713, found 365.8707.
to stir at -78 °C for one hour. Dimethyl disulfide (4.24 mmol)
was added dropwise to the mixture. The mixture was allowed to
warm to room temperature over night with stirring. The mixture
was concentrated under vacuum and the resulting concentrate
was dissolved in 4 mL MeOH. K2CO3 (3.50 mmol) was added to
the mixture. The mixture was allowed to stir at room temperature
overnight. The reaction mixture was concentrated under vacuum,
adsorbed onto silica gel, and purified via column
chromatography using hexanes as the eluent. Product was
7-bromo-3-iodo-2-phenyl-benzothiophene (76). Product was
o
1
isolated as a white solid: mp 98-99 C; H NMR (400 MHz,
chloroform-d) δ 7.36 (t, J = 8.0 Hz, 1H), 7.45-7.51 (m, 3H), 7.56
(d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.2, 2H), 7.79 (d, J = 8.4 Hz,
1H); 13C NMR (100 MHz, chloroform-d) δ 79.6, 115.2, 125.3,
126.5, 128.0, 128.6, 129.2, 130.0, 134. 2, 140.6, 142.7, 143.4; IR
(neat) 3020.2, 2400.7, 1216.8, 929.1, 770.8, 669.3. HRMS (EI+,
m/z) calcd for (C14H8BrIS)+ 413.8575, found 413.8578.
1
isolated as a colorless oil; H NMR (400 MHz, chloroform-d) δ
2.49 (s, 3H), 3.79 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.154 (t, J =
7.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
chloroform-d) δ 15.6, 79.6, 83.6, 88.8, 122.7, 126.8, 128.3,
129.8, 145.1; IR (neat) 3273.5, 2920.5, 2851.0, 1568.3, 1544.9,
1429.6, 1195.5, 1080.4, 969.9, 957.0, 762.3, 722.1, 705.0. HRMS
(EI+, m/z) calcd for (C9H7BrS)+ 225.9452, found 225.9443.
Synthesis
benzene (47).
of
1-(2,2-dibromovinyl)-2-methylsulfanyl-
A vial containing CBr4 (3.0 mmol) and aldehyde (3.0 mmol)
in 8 mL of DCM was cooled to 0 °C. A mixutre of PPh3 (6.0
mmol) in 4 mL DCM was added dropwise to the reaction mixture
with stirring. The mixture was allowed to warm to room
temperature. The mixture was concentrated under vacuum,
adsorbed onto silica gel, and purified via column
chromatography using hexanes as an eluent. Product was isolated
as an off-white solid: mp 49-50 oC; 1H NMR (400 MHz,
chloroform-d) δ 2.48 (s, 3H) 7.21 (t, J = 7.6 Hz, 1H) 7.28-7.37
(m, 2H) 7.52 (d, J = 7.6 Hz, 1H) 7.58 (s, 1H); 13C NMR (100
MHz, chloroform-d) δ 16.2, 92.6, 125.1, 126.3, 129.1, 129.3,
134.9, 135.5, 137.7; IR (neat) 1585.9, 1458.7, 1435.0, 1220.0,
1069.8, 1046.0, 953.4, 937.7, 874.5, 836.7, 790.6, 772.4, 737.1.
HRMS (EI+, m/z) calcd for (C9H8Br2S)+ 305.8713, found
305.8707.28
Synthesis
of
1-bromo-3-methylsulfanyl-2-(2-
phenylethynyl)benzene (52).
To vial containing
a
a
1-bromo-3-methylsulfanyl-2-(2-
phenylethynyl)benzene (0.634 mmol) and iodobenzene (1.90
mmol) in 5 mL of Et3N, PdCl2(PPh3)2 (0.032 mmol) and CuI
(0.032 mmol ) were added. The mixture was allowed to stir at
room temperature overnight. The reaction mixture was
concentrated under vacuum, adsorbed to silica gel, and purified
via column chromatography using hexanes as the eluent. Product
was isolated as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ
2.50 (s, 3H), 7.09-7.15 (m, 2H), 7.37-7.40 (m, 4H), 7.62-7.65 (m,
2H); 13C NMR (100 MHz, chloroform-d) δ 15.6, 86.0, 100.9,
122.6, 122.8, 123.0, 126.4, 128.2, 128.5, 128.9, 129.2, 131.9,
144.5; IR (neat) 3019.9, 2400.5, 1598.8, 1571.6, 1543.8, 1491.0,
1440.1, 1396.9, 1216.0, 1098.1, 929.0, 871.8, 849.8, 756.8,
690.3, 669.09. HRMS (EI+, m/z) calcd for (C15H11BrS)+
301.9765, found 301.9767.
Synthesis of 1-(2-bromoethynyl)-2-methylsulfanyl-benzene
(48).
A
vial containing 1-(2,2-dibromovinyl)-2-methylsulfanyl-
benzene (0.27 mmol) in 1 mL of DMSO was cooled to 15 °C. A
mixture of DBU (0.27 mmol) in 1 mL of DMSO was added
dropwise to the reaction mixture. The mixture was extracted with
water, concentrated under vacuum, and purifed via column
chromatography using hexanes as an eluent. Product was isolated
General procedure for the synthesis of thioanisoles 55 and
56.21
1
as a yellow liquid; H NMR (400 MHz, chloroform-d) δ 2.48 (s,
A 50 mL RBF containing 4(5)-bromo-2-iodoaniline (1.0
mmol) and dimethyl disulfide (1.0 mmol) in 3 mL CH3CN was
heated to reflux with stirring. Tert-butyl nitrite (1.0 mmol) was
added dropwise to the reaction mixture. The mixture was allowed
to reflux for one hour and was monitored to completion via TLC.
The reaction mixture was concentrated under vacuum, adsorbed
onto silica gel, and purified via column chromatography using
hexanes as the eluent.
3H), 7.07 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.30 (t, J
= 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
chloroform-d) δ 15.5, 56.4, 78.1, 121.3, 124.6, 129.5, 133.3,
142.5; IR (neat) 2919.5, 2193.5, 1995.7, 1582.3, 1460.1, 1434.7,
1070.4, 1038.4, 749.5. HRMS (EI+, m/z) calcd for (C9H7BrS)+
225.9452, found 225.9450.
Synthesis of 2-(2,6-dibromophenyl)ethynyl trimethylsilane
(50).
4-bromo-2-iodo-1-methylsulfanyl-benzene (55). Product was
isolated as an orange liquid; 1H NMR (400 MHz, chloroform-d) δ
2.44 (s, 3H), 6.94 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H),
7.91 (s, 1H); 13C NMR (100 MHz, chloroform-d) δ 17.3, 97.6,
118.1, 125.9, 131.7, 141.1, 142.6; IR (neat) 2982.6, 2916.8,
2849.4, 1639.8, 1554.5, 1537.7, 1430.0, 1356.6, 1246.9, 1109.4,
1085.5, 1011.7, 869.6, 799.6, 751.2. HRMS (EI+, m/z) calcd for
(C7H6BrIS)+ 327.8418, found 327.8419.
Under anhydrous conditions, a 50 mL RBF containing 1,3-
dibromo-2-iodobenzene (2.0 mmol), Pd(PPh3)4 (0.10 mmol), and
CuI (0.10 mmol) in 10 mL of triethylamine was equipped with a
reflux condenser. TMS-acetylene (2.0 mmol) was added
dropwise to the mixture. The reaction mixture was heated to 70
°C and was allowed to stir overnight. The mixture was
concentrated under vacuum, adsorbed onto silica gel, and purifed
via column chromatography using hexanes as an eluent. Product
was isolated as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ
0.301 (s, 9H), 6.99 (t, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H).
Other characterization data are in good agreement with the
previous reported data.29
4-bromo-1-iodo-2-methylsulfanyl-benzene (56). Product was
o
1
isolated as an orange solid: mp 53-55 C; H NMR (400 MHz,
chloroform-d) δ 2.46 (s, 3H), 6.96 (d, J = 8.0 Hz, 1H), 7.15 (s,
1H), 7.59 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, chloroform-
d) δ 17.1, 94.9, 123.3, 127.3, 129.0, 140.4, 145.8; IR (neat)
1553.8, 1435.2, 1356.5, 1246.6, 1219.9, 1089.9, 1072.9, 1002.2,
845.9, 800.4, 768.1. HRMS (EI+, m/z) calcd for (C7H6BrIS)+
327.8418, found 327.8422.
Synthesis of 1-bromo-2-ethynyl-3-methylsulfanyl-benzene
(51).
Under anhydrous conditions,
a
mixutre of 2-(2,6-
Synthesis of 1-bromo-3-iodo-2-methylsulfanyl-benzene
(60).
dibromophenyl)ethynyl trimethylsilane (2.12 mmol) and 10 mL
of THF was cooled to -78 °C. n-butyllithium (2.33 mmol) was

A solution of 1-bromo-3-iodobenzene (2.56 mL, 10.0 mmol)
Authors are also grateful to Dr. Tim Royappa for his help and
support throughout the project.
ACCEPTED MANUSCRIPT
in anhydrous THF (20 mL) was cooled to -78 °C using acetone-
dry ice bath. To this solution LDA (20 mL, 1.5 M in THF, 30.0
mmol) was added dropwise. After stirring for 1h, methyldisulfide
(2.88 mL, 32.0 mmol) was added dropwise, and the mixture was
allowed to come to room temperature and stirred overnight. After
workup with a saturated NH4Cl solution, the mixture was
extracted with dichloromethane. The organic layer was separated,
dried over MgSO4, concentrated under vacuum and purified via
column chromatography. The product was isolated as a yellow
oil; 1H NMR (400 MHz, chloroform-d) δ 2.43 (s, 1H) 6.78 (t, J =
7.6 Hz, 1H) 7.64 (d, J = 8.0 Hz, 1H) 7.88 (d, J = 8.0 Hz, 1H).
Other characterization data are in good agreement with the
previous reported data.21
References and notes
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S. A.; Nagaraja, B. M. Eur. J. Med. Chem. 2017, 138, 1002-1033.
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Med. Chem. 2011, 46, 3434-3443. (e) Staples, M. K.; Grange, R.
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Eur. J. Med. Chem. 2015, 90, 379-393. (m) He, Y.; Xu, J.; Yu, Z.-
H.; Gunawan, A. M.; Wu, L.; Wang, L.; Zhang, Z.-Y. J. Med.
Chem. 2013, 56, 832-842.
2. (a) Kan, B.; Zhang, Q.; Liu, F.; Wan, X.; Wang, Y.; Ni, W.; Yang,
X.; Zhang, M.; Zhang, H.; Russell, T. P.; Chen, Y. Chem. Mater.
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General Procedure for the synthesis of alkyne 57, 58 and
61.
To
a vial containing 1-bromo-3-iodo-2-methylsulfanyl-
benzene (0.658 mmol) in 4 mL of Et3N, phenylacetylene (0.790
mmol), PdCl2(PPh3)2 (0.013 mmol), and CuI (0.026 mmol) were
added. The reaction mixture was allowed to stir at room
temperature overnight. The reaction mixture was concentrated
under vacuum, adsorbed onto silica gel, and purified via column
chromatography using hexanes as an eluent.
4-bromo-1-methylsulfanyl-2-(2-phenylethynyl)benzene (57).
o
1
Product was isolated as a yellow solid: mp 44-46 C; H NMR
(400 MHz, chloroform-d) δ 2.50 (s, 3H), 7.03 (d, J = 8.8 Hz,
1H), 7.35-7.42 (m, 4H), 7.56-7.62 (m, 4H); 13C NMR (100 MHz,
chloroform-d) δ 15.4, 85.7, 97.2, 117.6, 122.9, 123.4, 125.8,
128.5, 128.9, 131.7, 131.8, 134.7, 141.1; IR (neat) 1597.3,
1571.0, 1490.8, 1442.1, 1431.3, 1387.3, 1251.0, 1219.8, 1089.0,
1059.3, 877.7, 806.1, 772.2, 757.4, 686.4. HRMS (EI+, m/z)
calcd for (C15H11BrS)+ 301.9765 found 301.9760.
4-bromo-2-methylsulfanyl-1-(2-phenylethynyl)benzene (58).
o
1
Product was isolated as a yellow solid: mp 75-77 C; H NMR
(400 MHz, chloroform-d) δ 2.45 (s, 3H), 7.14-7.22 (m, 2H),
7.25-7.32 (m, 4H), 7.50-7.53 (m, 2H); 13C NMR (100 MHz,
chloroform-d) δ 15.2, 86.1, 97.1, 120.1, 123.0, 123.1, 126.6,
127.4, 128.5, 128.7, 131.7, 133.3, 144.2; IR (neat) 1569.9,
1488.63, 1458.0, 1439.8, 1375.9, 1219.84, 1084.9, 1067.2, 850.8,
816.1, 772.3, 753.0, 690.2. HRMS (EI+, m/z) calcd for
(C15H11BrS)+ 301.9765, found 301.9757.
1-bromo-2-methylsulfanyl-3-(2-phenylethynyl)benzene (61).
Product was isolated as a yellow oil; 1H NMR (400 MHz,
chloroform-d) δ 2.58 (s, 3H), 7.12 (t, J = 7.6 Hz, 1H), 7.37 (t, J =
3.6 Hz, 3H), 7.52-7.61 (m, 4H); 13C NMR (100 MHz,
chloroform-d) δ 19.2, 88.4, 94.9, 123.2, 128.7, 128.9, 129.2,
130.4, 130.6, 131.9, 132.6, 133.4, 139.5; IR (neat) 3019.9,
2400.5, 1598.8, 1571.6, 1543.8, 1491.0, 1440.1, 1396.9, 1216.0,
1098.1, 929.0, 871.8, 849.8, 756.8, 690.3, 669.09. HRMS (EI+,
m/z) calcd for (C15H11BrS)+ 301.9765, found 301.9760.
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Acknowledgments
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We are thankful to Research Corporation for Science
Advancement for a Cottrell College Science Award (ID 23248).
The research was 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 appreciative of generous support provided by
University of West Florida (UWF), UWF’s Office of Research
and Sponsored Programs and Office of Undergraduate Research.
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