Mercury(II)-catalyzed cyclization of 2-alkynylphenyl alkyl sulfoxides provides 3-acylbenzo[b]thiophenes

Article abstract of DOI:10.1002/chem.201202704

Ring cyclization: A mercury-catalyzed cyclization reaction to provide 3-benzoylbenzo[b]thiophenes was achieved in good yields by treatment of 2-alkynylphenyl alkyl sulfoxides with mercury chloride and 2,3-dichloro-5,6- dicyano-1,4-benzoquinone (DDQ) in be

Full text of DOI:10.1002/chem.201202704

DOI: 10.1002/chem.201202704
Mercury(II)-Catalyzed Cyclization of 2-Alkynylphenyl Alkyl Sulfoxides
Provides 3-Acylbenzo[b]thiophenes
Cheng-Han Lin, Chin-Chau Chen, and Ming-Jung Wu*[a]
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Chem. Eur. J. 2013, 19, 2578 – 2581

COMMUNICATION
Molecules that contain the benzo[b]thiophene substruc-
ture often exhibit a broad spectrum of biological activities.[1]
For instance, raloxifene (1) and compound 2 have been re-
Scheme 1. Proposed synthesis of benzothiopyranones 4 or 3-acylbenzo[b]-
thiophenes 5.
Table 1. Attempted for the cyclization of 3a.
ported as unique selective estrogen receptor modu-
lators (SERMs) and antitubulin agents.[2] Recently,
raloxifene was found to be as effective as tamoxifen
in reducing the risk of invasive breast cancer and
has lower risk of thromboembolic events and cata-
racts.[3] Therefore, benzo[b]thiophenes have attract-
ed much attention from synthetic organic chem-
ists.[4]
Recently, the utility of transition metals, especial-
ly gold, to catalyze the reaction of alkynes with sulf-
oxide to generate a-carbonyl carbenoid analogues
and their synthetic applications have been widely
studied.[5] We envisioned that transition-metal-cata-
lyzed intramolecular cyclization of 2-alkynylphenyl
alkyl sulfoxides 3 to generate the metal carbenoids
Entry Catalyst (+oxidant)
Equiv Solvent T [8C] t [h] Products (yield [%])
1
2
3
4
5
6
7
8
PPh3AuCl
PtCl2
PtCl2
0.1
0.2
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
CH2Cl2
CH2Cl2
dioxane
CH2Cl2
CH2Cl2
benzene reflux 24
CH2Cl2 RT 72
CH2Cl2 reflux 24
dioxane 80 24
RT
RT
80
RT
RT
72
24
0.5
72
72
6 (10)
6 (20)
6 (50)
Cu
N
NR[a]
CuCl2
SnCl4
HgCl2
HgCl2
HgCl2
HgCl2
HgCl2
NR[a]
NR[a]
5a (8)
5a (20)
5a (10)
5a (15)
5a (30)[c]
5a (70)
5a (55)
5a (50)
9
10
11
12
13
14
DCE[b] reflux 24
benzene reflux 24
benzene reflux 24
benzene reflux 24
benzene reflux 24
HgCl2 (+DDQ)[d]
HgO (+DDQ)[d]
À
A or B followed by a sequential C H insertion and
oxidation would lead to either benzothiopyranones
4 or 3-acylbenzo[b]thiophenes 5 (Scheme 1).
HgACTHNUTRGNEUNG
(OAc)2 (+DDQ)[d]
[a] Starting material was recovered. [b] DCE=dichloroethane. [c] 42% yield of corre-
sponding dihydrothiophene (7a) isolated. [d] 1 equivalent of DDQ was added.
To test our hypothesis, 2-alkynylphenyl alkyl sulf-
oxide 3a was prepared starting from 2-iodothioani-
sole (s-1a) and 2-iodophenyl benzyl thioether (s-
1b), respectively (see the Supporting Information).
Initially, compound 3a was treated with PPh3AuCl
(10 mol%) in CH2Cl2 at room temperature for 72 h. The
only product obtained was 6 in 10% yield, and most of the
starting 3a was recovered (Table 1, entry 1). By using PtCl2
as the catalyst, a similar result was observed (Table 1,
entry 2). If the reaction was carried out in 1,4-dioxane under
reflux conditions for 30 min, compound 6 was obtained in
50% yield (Table 1, entry 3).[6] Copper catalysts, including
at room temperature for 72 h gave compound 5a in low but
encouraging yield (Table 1, entry 7).
To optimize the reaction conditions, reactions were car-
ried out with different solvents and at various temperatures.
The results are summarized in Table 1. When the reaction of
3a with HgCl2 (10 mol%) was carried out in CH2Cl2 heated
to reflux for 24 h, the yield of 5a was increased to 20%
(Table 1, entry 8). 1,4-Dioxane was found to be less effective
for benzothiophene formation than CH2Cl2 (Table 1,
entry 9). 1,2-Dichloroethane heated to reflux was also em-
ployed in this study but the yield was not improved
(Table 1, entry 10). Heating the reaction mixture in DMSO
at 808C led to a complicated mixture of the products. Other
solvents, including toluene, DMF, THF, and CH3OH, were
not effective for the product formation. Ultimately, benzene
was found to be the most effective for the product forma-
tion. The reaction of 3a with HgCl2 (10 mol%) in benzene
heated to reflux for 24 h provided compound 5a in 30%
yield along with 42% of dihydrobenzothiophene 7a
(Table 1, entry 11). Upon introduction of 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ; 1 equiv) into the reaction
mixture, the desired product 5a was obtained in 70% yield
CuACHTUNGTRENNUNG(OTf)2 and CuCl2 as well as SnCl4 were found to be inef-
fective in catalyzing this reaction (Table 1, entries 4–6).
However, reaction of 3a with HgCl2 (10 mol%) in CH2Cl2
[a] C.-H. Lin, Dr. C.-C. Chen, Prof. Dr. M.-J. Wu
Department of Chemistry
National Sun Yat-sen University, Kaohsiung, Taiwan
804 Room 3003, College of Science, No. 70
Lienhai Rd., Kaohsiung 80424 (Taiwan)
Fax: (886)7-5252000-3914
E-mail: mijuwu@faculty.nsysu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202704.
Chem. Eur. J. 2013, 19, 2578 – 2581
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2579

M.-J. Wu et al.
(Table 1, entry 12). HgO and HgACHTNUGTRENUNG(OAc)2 were also employed
in this study and found to be less effective than HgCl2 for
the formation of 3-benzoylbenzo[b]thiophene (5a; Table 1,
entries 13 and 14).
With the optimized reaction conditions in hand, the mer-
cury-catalyzed cyclization reaction was extended to other 2-
alkynylphenyl methyl sulfoxides 3b–k. The results are sum-
marized in Table 2. All substrates that bear either alkyl or
cannot conclude the a-carbonyl carbenoid is the key
intermediate for the product formation.
Table 2. Synthesis of 3-acylbenzo[b]thiophenes by optimized reaction conditions.
In conclusion, we have demonstrated that 3-acyl-
benzo[b]thiophenes can easily be prepared by the
cyclization of 2-alkynylphenyl alkyl sulfoxides cata-
lyzed by mercury chloride. The reaction mechanism
is not clear at this stage. Further studies are needed
to conclude the reaction mechanism. Efforts to
apply this cyclization reaction to the synthesis of
pharmaceutically important compounds are also
under investigation.
Entry
R1
R2
R3
t [h]
Products (yield [%])
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Ph
H
H
H
H
H
H
H
H
H
24
24
24
24
36
24
48
24
24
24
24
24
24
36
48
24
5a (67)
5b (70)
5c (72)
5d (72)
5e (68)
5 f (54)
5g (50)
5h (65)
5i (63)
5j (66)
5k (65)
5l (80)
5m (85)
5n (78)
5o (72)
5p (75)
4-CH3C6H4
4-CH3OC6H4
2-CH3OC6H4
3,4,5-(CH3O)3C6H2
4-BrC6H4
4-NO2C6H4
nPr
nPen
iBu
tBu
Ph
Experimental Section
9
HgCl2 (5.4 mg, 0.02 mol) and DDQ (45 mg, 0.2 mmol) were
added to a stirred solution of sulfoxides 3a–p (0.2 mmol) in
benzene (20 mL). The resulting solution was heated to reflux
and stirred at this temperature for 24 to 48 h (monitored by
TLC). After cooling to room temperature, the solution was fil-
tered through a pad of silica gel and the solvent was removed.
The residue was purified by column chromatography on silica
gel (n-hexane/EtOAc 30:1 as eluent) to give 3-acylbenzo[b]-
thiophenes (5).
10
11
12
13
14
15
16
H
H
Ph
Ph
Ph
Ph
Ph
4-CH3OC6H4
3,4,5-(CH3O)3C6H2
4-NO2C6H4
tBu
aryl substituents on the terminal alkynes gave 3-arylcarbo-
nylbenzo[b]thiophenes in modest to good yields (50–72%).
The benzyl sulfoxides 3l–p were subjected to the optimized
reaction conditions to give 2-phenyl-3-arylcarbonylbenzo[b]-
thiophenes 5l–p in good yields (75–85%). The results indi-
cate that steric hindrance has very little influence on the re-
action. The tBu does not have a significant effect. Introduc-
ing a strong electron-withdrawing group, such as a nitro
group, into the phenyl ring on the terminal alkyne decreased
the reaction rate and the yield. Thus, cyclization of 3g and
3o required 48 h to go to completion; the yields are 50 and
72%, respectively.
Acknowledgements
We thank the National Science Council of the Republic of China for fi-
nancial support.
Keywords: benzothiophenes · cyclization · heterocycles ·
mercury chloride · rearrangement
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3-Acylbenzo[b]thiophenes
COMMUNICATION
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See the Supporting Information.
Received: July 27, 2012
Revised: December 14, 2012
Published online: January 18, 2013
Chem. Eur. J. 2013, 19, 2578 – 2581
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www.chemeurj.org
2581