Copper(II)-Catalyzed Single-Step Synthesis of Aryl Thiols from Aryl Halides and 1,2-Ethanedithiol

Article abstract of DOI:10.1002/adsc.201400941

A highly efficient transition metal-catalyzed single-step synthesis of aryl thiols from aryl halides has been developed employing copper(II) catalyst and 1,2-ethanedithiol. The key features are use of readily available reagents, a simple operation, and relatively mild reaction conditions. This new protocol shows a broad substrate scope with excellent functional group compatibility. A variety of aryl thiols are directly prepared from aryl halides in high yields. Furthermore, the aryl thiols are used in situ for the synthesis of more advanced molecules such as diaryl sulfides and benzothiophenes.

Full text of DOI:10.1002/adsc.201400941

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DOI: 10.1002/adsc.201400941
Copper(II)-Catalyzed Single-Step Synthesis of Aryl Thiols from
Aryl Halides and 1,2-Ethanedithiol
Yajun Liu,a,b Jihye Kim,a Heesun Seo,a Sunghyouk Park,b and Junghyun Chaea,*
a
Department of Chemistry and Research Institute of Basic Sciences, Sungshin Womenꢀs University, Seoul, Korea
Fax : (+82)-2-920-2547; phone: (+82)-2-920-7660; e-mail: jchae@sungshin.ac.kr
College of Pharmacy, Seoul National University, Seoul, Korea
b
Received: September 25, 2014; Published online: && &&, 0000
Dedicated to Prof. S. L. Buchwald on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400941.
Abstract: A highly efficient transition metal-cata-
lyzed single-step synthesis of aryl thiols from aryl
halides has been developed employing copper(II)
catalyst and 1,2-ethanedithiol. The key features are
use of readily available reagents, a simple opera-
tion, and relatively mild reaction conditions. This
new protocol shows a broad substrate scope with
excellent functional group compatibility. A variety
of aryl thiols are directly prepared from aryl halides
in high yields. Furthermore, the aryl thiols are used
in situ for the synthesis of more advanced molecules
such as diaryl sulfides and benzothiophenes.
However, this reaction also runs at very high temper-
ature, and it is narrowly applicable to simple aryl hal-
ides.
Attempts at the direct introduction of a thiol group
into aromatic rings via transition metal-catalyzed re-
actions have been unfruitful, whereas the correspond-
ing formations of amine[9] and hydroxy[10] groups are
known. Apart from the well-known ꢁpoisonousꢀ char-
acter of sulfur to metal catalysts,[11] it is presumably
due to the high reactivity of aryl thiols, producing
side products; even if aryl thiols are generated, they
further react with aryl halides and/or they are easily
oxidized during the coupling process.[1c] In fact, metal
sulfides such as NaSH and Na2S always gives diaryl
sulfides and diaryl disulfides in the coupling reaction
with aryl halides.[12] Therefore, surrogates for the sul-
fide ion, which can cross-couple with aryl halides and
later liberate thiols by additional transformation, have
been sought over the past few decades (Scheme 1). In
the earlier work published by Takagi,[13] thiourea re-
Keywords: alkanedithiols; aryl thiols; benzothio-
À
phenes; copper(II) catalysts; C S cross-coupling;
diaryl sulfides
Aryl thiols are important structural motifs and build- acted with aryl iodides in the presence of a nickel(0)
ing blocks for both natural products and synthetic catalyst and the resulting S-aryl-isothiouronium salt
compounds that show diverse activities ranging from was further hydrolyzed to give aryl thiols. Other thiol
pharmaceuticals to polymers and functional materi- surrogates later reported are mostly based on the pro-
als.[1] Yet, effective synthetic methods for aryl thiols tection chemistry of thiols:[14] thiobenzoic acid, pyri-
are still much needed due to the scarcity of concise dine-ethanethiol, isooctyl 3-mercaptopropionate, and
and mild conditions leading to a wide spectrum of triisopropylsilanethiol. While these reports provided
aryl thiols. Most of conventional methods including proof-of-concepts for aryl thiol preparation with
Leuckart thiophenol synthesis,[2] Newman–Kwart re- a few examples, more reliable synthetic methods were
action,[3] and Schoenberg reaction[4] require multistep developed very recently. Ma[12b] and Feng[15] employed
syntheses involving diazotization and/or thermal rear- sulfur powder and Guo[16] applied sodium thiosulfate
rangement at 200–3008C. Reduction of arylsulfonyl with copper and palladium catalysts, respectively.
chlorides[5] or diaryl polysulfides[6] is often employed, Their coupling products are polysulfides, which need
but it is also unfavorable due to the laborious prepa- to be reduced to afford the desired aryl thiols. Al-
ration of the specific precursors as well as harsh con- though these transition metal-catalyzed protocols are
ditions. Synthetic route from readily available aryl milder than the traditional methods, they still have
halides has been reported using either H2S[7] or excess much room for improvement. First of all, more effi-
alkyl thiolates[8] via aromatic nucleophilic substitution. cient single-step reactions with an atom-economical
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Scheme 1. Synthesis of aryl thiols via transition metal-catalyzed C S cross-coupling reactions.
sulfur source would be desirable, as the extra reaction cluding para-tolyl disulfide (3a’) and di-para-tolyl sul-
steps and/or by-products from the surrogates make fide (3a’’) were not observed. Diarylated 1,2-ethanedi-
À
these methods less attractive. The isolation of aryl thiol, which was expected from a C S coupling reac-
thiols from the reaction mixture is also problematic tion at both thiol groups, was not detected, either.
due to their highly oxidizable nature, unless the yield However, di-para-tolyl sulfide was formed in small
is high in each step and the reaction mixture contains amount (ca. 5%) when DMF was used as solvent
only readily separable by-products. Copper is often (entry 3). Polar solvents other than DMSO usually
the metal of choice but it generally works only with showed low conversion and yield (entries 3–5), and
aryl iodides. One may broaden the substrate scope to non-polar solvents such as toluene were essentially in-
aryl bromides by using an expensive palladium-phos- effective (entry 6). Adding water seems to help solu-
phine system, but both palladium and copper catalytic bilize the inorganic base, thereby slightly improving
methods still show limited tolerance for functional the yield (entry 7). Further optimization with various
groups. Herein, we report a highly efficient transition copper salts revealed that both copper(I) and cop-
metal-catalyzed single-step synthesis of aryl thiols per(II) salts are generally effective and quantitative
from aryl halides using a copper(II) catalyst and 1,2- conversion from 1a into 3a can be achieved with
ethanedithiol. Our newly developed protocol requires Cu(OH)2
and
CuSO4·5H2O
(entries 8–14).
no additional steps or reagents, and is applicable to CuSO4·5H2O was chosen as the catalyst for further
a broad range of aryl iodides and bromides. More- studies because it is air- and moisture-stable, readily
over, the generated aryl thiols can be used in situ for available, and easily removed during aqueous work-
the synthesis of more advanced molecules.
up. Strong bases such as KOH, NaOH and CsOH
In search for a suitable thiol surrogate for aryl thiol were necessary for the transformation (entries 13, 15,
synthesis, we discovered that alkanedithiols can cross- and 16) while weak bases such as K2CO3, K3PO4, and
couple with aryl halides under copper catalytic condi- Cs2CO3 showed poor results and a small amount of
tions. Intriguingly, we found that aryl thiols are direct- para-tolyl disulfide (1–3%) was detected (entries 17–
ly obtained when certain alkanedithiols are empolyed, 19). However, when Cs2CO3 was used at the elevated
which is especially so with 1,2-ethanedithiol. Thus, we temperature up to 1108C, complete conversion of
set out to investigate the optimal conditions with 1,2- starting material and 90% yield of the desired thiol
ethanedithiol and 4-iodotoluene, studying factors such was achieved, suggesting that Cs2CO3 can be used in
as copper salt, solvent, base, equivalents of reagents, place of KOH for those substrates sensitive to strong
reaction time, and temperature (Table 1). Our initial bases (entry 19). Reducing the amount of 1,2-ethane-
attempt using 5 mol% of CuI and 5 equivalents of dithiol and/or base, shortening the reaction time, and
KOH in DMSO at 908C for 20 h resulted in the for- lowering the reaction temperature caused negative ef-
mation of 4-methylbenzenethiol (3a) in 87% fects (entries 20–24). Nonetheless, 1a was effectively
(entry 2). To our delight, undesired by-products in- converted into 3a with reduced loading of 1,2-ethane-
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Copper(II)-Catalyzed Single-Step Synthesis of Aryl Thiols
Table 1. Optimization of thiolation conditions.[a]
other aliphatic dithiols (2b, 2d, 2e) and 2-mercapto-
AHCTUNGTRENNUNG
ethanol (2f) gave 4 as the major product.[17] When
these aryl alkyl sulfides such as 4b, 4d, 4e and 4f were
isolated and treated with KOH in DMSO at 1208C,
3a was generated in 30–80% yields. Such a conversion
seems to proceed via intramolecular SN2 cleavage re-
action as 6- and 7-membered cyclic thioethers were
detected by GC-MS in the reaction of 4d and 4e, re-
spectively. In addition, it was observed that tetrahy-
drothiophene was formed along with aryl thiol 3a
when 1,4-butanedithiol (2c) was reacted with 1a.[18]
Inspired by these experimental results, we reached
a plausible reaction pathway for the formation of aryl
Entry [Cu]
Solvent
Base
Yield [%][b]
1
–
DMSO
DMSO
DMF
H2O
dioxane
toluene
DMSO/H2O KOH
DMSO/H2O KOH
DMSO/H2O KOH
DMSO/H2O KOH
DMSO/H2O KOH
DMSO/H2O KOH
KOH
KOH
KOH
KOH
KOH
KOH
<5
87
31
37
<5
0
92
97
76
96
96
99
99
92
2
CuI
À
thiols (Scheme 3). The C(aryl) S bond between aryl
3
CuI
halide and aliphatic dithiols is formed in the presence
of copper catalyst to afford aryl alkyl sulfide, and
4
CuI
5
CuI
À
then the S C(alkyl) bond is cleaved via an intramo-
6
CuI
lecular SN2 reaction by the terminal alkyl thiolate
under the basic conditions. Presumably, the driving
forces of the cleavage reaction are intramolecular
7
CuI
8
9
CuBr
Cu2O
CuCl2
Cu(OAc)2
Cu(OH)2
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
22[f]
23[g]
24[h]
thio
thio
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
thiol can be obtained in a single-step or not would
depend on the efficiency of the intramolecular SN2 re-
action. Therefore, the results shown in Scheme 2 are
consistent with the fact that 3- and 5-membered ring
formation is more favored than ring formation of
other sizes. Weaker nucleophilic alkoxides as in case
of 4f are less efficient than the corresponding thio-
lates for the cleavage reaction.
We then explored the scope of our developed trans-
formation and the results are summarized in Table 2.
Good to excellent yields were obtained for a broad
range of substrates. Aryl iodides were readily convert-
CuSO4·5H2O DMSO/H2O KOH
CuO DMSO/H2O KOH
CuSO4·5H2O DMSO/H2O NaOH 91
CuSO4·5H2O DMSO/H2O CsOH 98
CuSO4·5H2O DMSO/H2O K2CO3 35
CuSO4·5H2O DMSO/H2O K3PO4 67
CuSO4·5H2O DMSO/H2O Cs2CO3 70, 90[c]
CuSO4·5H2O DMSO/H2O KOH
CuSO4·5H2O DMSO/H2O KOH
CuSO4·5H2O DMSO/H2O KOH
CuSO4·5H2O DMSO/H2O KOH
CuSO4·5H2O DMSO/H2O KOH
86, 96[c]
87
69
95
66
[a]
Reaction conditions: 1a (1 mmol), 2a (2 mmol), [Cu] ed into aryl thiols regardless of electronic and steric
(5 mol%), base (5 equiv.), DMSO (2 mL) or DMSO/H2O
(2 mL/0.2 mL), 908C, 20 h.
GC yields using n-dodecane as internal stardard.
At 1108C.
With 1.2 equiv. of 2a.
With 4 equiv. of KOH.
With 1.2 equiv. of 2a and 3 equiv. of KOH.
For 12 h.
At 708C.
effects of substituents, while aryl bromides possessing
electron-neutral and electron-withdrawing groups
were transformed at an elevated temperature
(1108C). Simple alkyl substituted aryl iodides, biphen-
yl iodide, 1- and 2-iodonaphthalenes, and some of
their bromo equivalents reacted in very good to excel-
lent yields (3a–3f). Free amine, phenolic hydroxy and
aliphatic hydroxy groups were compatible under the
reaction conditions (3g–3l) while competitive N- or
O-arylation did not occur. In case of alkoxy-substitut-
[b]
[c]
[d]
[e]
[f]
[g]
[h]
dithiol (1.2 equiv.) at higher temperature (1108C) ed substrates such as 3m, 3n, and 3o, cleavage of alkyl
(entry 20). These optimization experiments led to the group by thiolate was observed in less than 5%. The
following reaction conditions: ArI (1 mmol), 1,2-etha- preparation of 3-hydroxythiophenol (3j) using our
nedithiol (2 mmol), CuSO4·5H2O (5 mol%), KOH single-step catalytic system is noteworthy because it is
(5 mmol), DMSO/H2O (2 mL/0.2 mL), 908C, 20 h.
an important synthetic intermediate of raloxifene, an
In order to obtain an insight into our reaction path- osteoporosis drug, but has been prepared via a labori-
way, several aliphatic dithiols of different chain ous multi-step process.[19] In fact, our catalytic system
lengths and 2-mercaptoethanol were tested under the showed an excellent functional group tolerance, thus
standard conditions (Scheme 2). Depending on the allowing an access to aryl thiols which are otherwise
sulfur sources (2a–f), either aryl thiol 3a or aryl alkyl difficult to obtain. These include aryl thiols possessing
sulfide 4 was produced; 1,2-ethanedithiol (2a) and carbonyl, aldehyde, ester, and nitrile groups (3p–3t,
1,4-butanedithiol (2c) gave 3a as the only product, but 3v, and 3-w). For these aryl thiols, Cs2CO3 in DMSO
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Scheme 2. Coupling reaction of aliphatic dithiols of different lengths; GC yields in the parentheses refer to 3a and 4, respec-
tively, with n-dodecane as internal standard.
dized to disulfides during work-up and they required
proper handling for the isolation.[20]
Aryl thiols were directly subjected to alkylation
without purification (Table 3). The excellent yields
were observed in the one-pot two-step reactions for
5q and 5ab. The high yields suggest that the corre-
sponding aryl thiols (3q and 3ab) were produced
nearly quantitatively, and the lower isolation yields
obtained for these aryl thiols were due to the instabil-
ity during the work-up process (vide supra). Some of
the water-soluble heterocyclic thiols were also alkylat-
Scheme 3. Proposed reaction pathway.
ed in situ to afford the corresponding alkyl thioethers
(5ag and 5ah), implying these heterocyclic halides are
in place of KOH in aqueous DMSO turned out to be also effective substrates for the conversion to thiols.
more effective: hydrolysis of ester, amide, and nitrile We then wished to examine whether the reaction
was greatly suppressed. For example, less than 10% mixtures containing copper(II) catalyst and aryl thiols
of mercaptobenzoic acid was observed in the reaction can be directly used for the coupling reaction with
of a substrate with an ester group (3t). Halogen-sub- aryl iodides to afford diaryl sulfides. A good deal of
stituted substrates were also transformed into the de- experiments led us to develop the efficient process for
sired aryl thiols, and the cross-coupling occurred at both symmetrical and unsymmetrical diaryl sulfides
the carbon bearing the more reactive halide (I>Br> which are shown in Table 4. Diaryl sulfides are often
Cl), exhibiting the selectivity of the reaction (3z–3ab). synthesized from aryl thiols and aryl halides using
Aryl chlorides with strong electron-withdrawing metal catalysts,[21] but the product diversity is greatly
groups such as trifluromethyl and nitro reacted with limited by the availability of aryl thiols. Alternative
À
1,2-ethanedithiol without a copper catalyst, but the methods employing double C S couplings between
conversions and yields were improved under the cata- two aryl halides and H2S equivalents such as thioace-
lytic conditions (3ac and 3ad). Heterocyclic com- tate, thiourea, ethyl xanthogenate, TIPS-SH, KSCN,
pounds such as 2-bromoquinoline and 2-bromobenzo- Na2S have been reported,[12a,14c,22,23] and all these meth-
thiazole also afforded the corresponding products in ods essentially endeavor to generate aryl thiols in situ
over 90% yield (3ae and 3af). Throughout the study, in various indirect ways. However, contrary to sym-
we observed that the thiolation proceeded smoothly metrical diaryl sulfides, the one-pot sequential prepa-
regardless of the substitution position (ortho vs. meta ration of unsymmetrical diaryl sulfides still suffers
vs. para) as demonstrated with iodophenols (3i–3k) from either expensive operations using palladium
and haloacetophenones (3p–3r). Moreover, various and/or costly ligands or limited substrate scope. In
substituents at the ortho position can be tolerated re- this regard, the direct synthesis of aryl thiols and their
gardless of their electronic nature (3c, 3h, 3k, 3n, 3r, in situ use for diaryl sulfides under ligand-free copper-
3aa, 3ac). Incidentally, we found that the aryl thiols catalytic conditions developed by us is indeed a grati-
containing electron-withdrawing groups at the meta fying advance. Aryl iodides reacted with 0.55 equiv.
position such as 3q, 3w, 3y and 3ab were readily oxi- 1,2-ethanedithiol with 5 mol% copper sulfate in DMF
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Copper(II)-Catalyzed Single-Step Synthesis of Aryl Thiols
Table 2. Thiolation of aryl halides with 1,2-ethanedithiol.[a]
Table 3. In situ alkylation of aryl thiols.[a]
[a]
Reaction conditions: After thiolation is completed, R’X
(3 mmol) and DMF (1 mL) were added and the mixture
was stirred for 5 h at room temperature; overall two-step
yields of isolated products.
and H2O at 1208C, furnishing a variety of symmetrical
diaryl sulfides with various functional groups in good
to excellent yields (6c–6ag). More significantly, un-
symmetrical diaryl sulfides were readily prepared by
adding the second aryl iodide in DMF into the reac-
tion mixture after the first aryl halide was trans-
formed to aryl thiol (7a–7ap). Addition of DMF was
À
beneficial for the second C S coupling and each step
reaction required a higher temperature for the com-
pletion. Under the developed conditions, the order of
adding aryl iodides was not important because most
aryl iodides can be used either at the first or second
step regardless of their electronic nature, providing
more freedom when designing sulfides. As demon-
strated in the synthesis of the aryl thiols in Table 2,
many functional groups including amine, hydroxy, ni-
trile, carboxyl, and halo groups were also compatible
with these one-pot reaction conditions. Heteroaryl
aryl sulfides were readily synthesized as well.
In addition, the in situ use of aryl thiols was further
explored for the synthesis of benzothiophenes.[24] Sev-
eral 2-arylbenzothiophenes, as examples, were synthe-
sized from aryl bromides bearing a phenylethynyl
group at the ortho position using the same protocol
for the aryl thiol synthesis (Scheme 4).
In summary, we have developed a highly efficient
transition metal-catalyzed single-step synthesis of aryl
thiols from aryl halides employing a copper(II) cata-
[a]
Reaction conditions: ArX (1 mmol), 2a (2 equiv.),
CuSO4·5H2O (5 mol%), KOH (5 equiv.), DMSO/H2O
(2 mL/0.2 mL), 20 h, 908C for ArI and 1108C for ArBr
and ArCl; yields of isolated products.
With 6 equiv. of KOH.
For 30 h.
With Cs2CO3 as base in DMSO (2 mL).
At 908C.
At 608C.
Without copper.
[b]
[c]
[d]
[e]
[f]
[g]
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Table 4. One-pot synthesis of symmetrical/unsymmetrical diaryl sulfides.[a]
[a]
Reaction conditions: [A] ArX (1 mmol), HSCH2CH2SH (0.55 equiv.), CuSO4·5H2O (5 mol%), KOH (5 equiv.), DMF/
H2O (2 mL/0.2 mL), 1208C, 18 h; [B] 1) ArX (1 mmol), HSCH2CH2SH (1 equiv.), CuSO4·5H2O (5 mol%), KOH
(5 equiv.), DMSO/H2O (2 mL/0.2 mL), 8 h, 1008C for ArI and 1108C for ArBr; 2) Ar’I (1.3 equiv.) in DMF (1 mL),
1208C, 18 h; yields of isolated products.
[b]
With Cs2CO3 as base in DMSO (2 mL).
lyst and 1,2-ethanedithiol in aqueous DMSO. The cat- choice of which is the key for the single-step transfor-
alyst of the reaction, CuSO4·5H2O, is one of the most mation to aryl thiols. A broad range of aryl iodides
À
readily available copper salts. The C S cross-coupling and bromides of various functional groups are directly
proceeds with various alkanedithiols, the proper converted into the corresponding aryl thiols without
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Copper(II)-Catalyzed Single-Step Synthesis of Aryl Thiols
MgSO4 and concentrated under vacuum. The crude product
was further purified by column chromatography to provide
the aryl alkyl sulfide.
General Procedure for Synthesis of Symmetrical
Diaryl Sulfides (Table 4)
To a test tube containing a magnetic stir bar was added aryl
halide (1 mmol), CuSO4·5H2O (12.5 mg, 0.05 mmol), KOH
(280 mg, 5 mmol), DMF (2 mL), and water (0.2 mL). After
flushing with argon, 1,2-ethanedithiol (0.05 mL, 0.55 mmol)
was added. The mixture was stirred in the preheated oil
bath at 1208C for 18 h. After being cooled to ambient tem-
perature, the reaction mixture was distributed in water and
ethyl acetate. The organic layer was separated and washed
with water and brine, dried over MgSO4 and concentrated
under vacuum. The crude product was further purified by
column chromatography to provide the desired symmetrical
diaryl sulfide.
General Procedure for Synthesis of Unsymmetrical
Diaryl Sulfides (Table 4)
Scheme 4. Synthesis of 2-aryl benzothiophenes.
To a test tube containing a magnetic stir bar was added aryl
halide (1 mmol), CuSO4·5H2O (12.5 mg, 0.05 mmol), KOH
(280 mg, 5 mmol), DMSO (2 mL), and water (0.2 mL; water
was not used in case of using Cs2CO3 as base). After flush-
ing with argon, 1,2-ethanedithiol (0.09 mL, 1 mmol) was
added. The mixture was stirred in the preheated oil bath at
1008C or 1108C for 8 h. After cooling to ambient tempera-
additional reaction steps or reagents, while by-prod-
ucts such as sulfides and disulfides are not formed.
Some of examples include aryl thiols which are com-
mercially unavailable and/or difficult to prepare via
previously known methods. Furthermore, the generat-
ed aryl thiols are used in situ for the synthesis of
more advanced molecules such as diaryl sulfides and ture, a solution of the second aryl halide (1.3 mmol) in
DMF (1 mL) was added. Then the reaction mixture was re-
heated to 1208C for 18 h. After being cooled to ambient
temperature, the reaction mixture was distributed in water
and ethyl acetate. The organic layer was separated and
washed with water and brine, dried over MgSO4 and con-
centrated under vacuum. The crude product was further pu-
rified by column chromatography to provide the desired un-
symmetrical diaryl sulfide.
benzothiophenes.
Experimental Section
General Procedure for Synthesis of Aryl Thiols
(Table 2)
To a test tube containing a magnetic stir bar was added aryl
halide (1 mmol), CuSO4·5H2O (12.5 mg, 0.05 mmol), KOH
(280 mg, 5 mmol) or Cs2CO3 (1.62 g, 5 mmol), DMSO
(2 mL), and water (0.2 mL; water was not used in case of
using Cs2CO3 as base). After flushing with argon, 1,2-etha-
nedithiol (0.18 mL, 2 mmol) was added. The mixture was
stirred in the preheated oil bath at 908C or 1108C for 20 h.
After being cooled to ambient temperature, the reaction
mixture was distributed in aqueous HCl (5%) and ethyl ace-
tate. The organic layer was separated and washed with
water and brine, dried over MgSO4 and concentrated under
vacuum. The crude product was further purified by column
chromatography to provide the desired aryl thiol.
General Procedure for Synthesis of 2-
Arylbenzothiophenes (Scheme 4)
To a test tube containing a magnetic stir bar under an argon
atmosphere was added 1-bromo-2-(phenylethynyl)benzene
(1 mmol), CuSO4·5H2O (12.5 mg, 0.05 mmol), KOH
(280 mg, 5 mmol), DMSO (2 mL), water (0.2 mL), and 1,2-
ethanedithiol (0.18 mL, 2 mmol). The mixture was stirred in
the preheated oil bath at 1108C for 20 h. After being cooled
to ambient temperature, the reaction mixture was distribut-
ed in water and ethyl acetate. The organic layer was separat-
ed and washed with water and brine, dried over MgSO4 and
concentrated under vacuum. The crude product was further
purified by column chromatography to provide the desired
2-arylbenzothiophene.
General Procedure for Synthesis of Aryl Alkyl
Sulfides (Table 3)
After the above thiolation was complete, the reaction mix-
ture was cooled to ambient temperature and alkyl halide
(3 mmol) in DMF (1 mL) was added. Then, the mixture was
stirred at room temperature for 5 h. The reaction mixture
was distributed in water and ethyl acetate. The organic layer
was separated and washed with water and brine, dried over
Acknowledgements
This work was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea
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funded by the Ministry of Education, Science and Technolo-
gy (NRF-2010-0025089).
C. Duan, Eur. J. Org. Chem. 2011, 7331–7338; b) Y.
Jiang, Y. Qin, S. Xie, X. Zhang, J. Dong, D. Ma, Org.
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8
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