CuI/TMEDA-catalyzed annulation of 2-bromo alkynylbenzenes with Na 2S: Synthesis of benzo[b]thiophenes

Article abstract of DOI:10.1021/jo201081v

A copper-catalyzed thiolation annulation reaction of 2-bromo alkynylbenzenes with sodium sulfide has been developed. In the presence of CuI and TMEDA, a variety of 2-substituted benzo[b]thiophenes were readily prepared in moderate to good yields by the reaction of 2-bromo alkynylbenzenes and Na₂S?9H₂O.

Full text of DOI:10.1021/jo201081v

NOTE
pubs.acs.org/joc
CuI/TMEDA-Catalyzed Annulation of 2-Bromo Alkynylbenzenes with
Na2S: Synthesis of Benzo[b]thiophenes
Lei-Lei Sun, Chen-Liang Deng, Ri-Yuan Tang, and Xing-Guo Zhang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
S Supporting Information
b
ABSTRACT: A copper-catalyzed thiolation annulation reaction
of 2-bromo alkynylbenzenes with sodium sulfide has been
developed. In the presence of CuI and TMEDA, a variety of
2-substituted benzo[b]thiophenes were readily prepared in mod-
erate to good yields by the reaction of 2-bromo alkynylbenzenes
and Na2S 9H2O.
3
enzo[b]thiophenes are an important class of heterocyclic
Scheme 1
B
compounds due to their wide range of biological properties1
and also various applications in materials science.2 The benzo-
[b]thiophene ring system and its derivatives are the core of numerous
medicinal molecules, such as clinically used raloxifene,3 arzoxifene,4
and zileuton.5 For this reason, synthesis of this privileged structure
has recently attracted much attention and many efficient methods
have been developed. Most of these approaches are focused on
(1) electrophilic cyclization reaction of o-alkynyl thioanisole6 and
(2) coupling cyclization reaction of o-bromo alkynylbenzenes
with various thiol surrogates upon lithiumꢀhalogen exchange at
ꢀ78 °C.7 In 2009, Takimiya and co-workers also reported the
synthesis of benzo[b]thiophene from the annulation of o-haloethy-
nylbenzene with sodium sulfide at 180 °C (Scheme 1, eq 1).8 How-
ever, the utility and applicability of the above reactions suffer from
the harsh reaction conditions. Recently, transition-metal-catalyzed
carbonꢀsulfur bond forming reactions have been extensively studied,9
which would provide a more convenient and efficient route for the
construction of the benzo[b]thiophene skeleton.10 Our group also
developed a copper-catalyzed double thiolation reaction of 1,
4-dihalides with metal sulfides for the synthesis of 2-trifluoromethyl
benzo[b]thiophenes and benzo[b]thiazoles.11 As a continuing
interest in the synthesis of sulfur-containing compounds,12 we
wish to prepare various different 2-substituted benzo[b]thiophenes
using a practical method. Herein, we report a copper-catalyzed
cyclization between 2-bromo alkynylbenzenes and easily avail-
able sodium sulfide for the synthesis of 2-substituted benzo[b]-
thiophenes (Scheme 1, eq 2).
salts could mediate the cyclization reaction (entries 2ꢀ6). CuI was
proved to be superior to other copper salts, including CuCl, CuBr,
Cu(OTf)2, and Cu(OAc)2. The target product 2a could be obtained
in 47% yield when substrate 1a was treated with Na2S and 10 mol %
of CuI in DMF at 80 °C (entry 3). Encouraged by these results, we
investigated various N,N-bidentate ligands, such as N,N,N0,N0-tetra-
methylethylenediamine (TMEDA), 1,10-phenanthroline (1,10-
phen), N,N0-dimethylethanediamine (DMEDA), and2,20-bipyridine
(entries7ꢀ10). To our delight, all of these ligands could promote the
thiolation annulation reaction and TMEDA provided the best result.
Treatment of substrate 1a with Na2S, 10 mol % of CuI, and 20 mol %
of TMEDA in DMF at 80 °C afforded the target product 2a in 83%
yield (entry 7). Finally, the effects of solvents and reaction tempera-
tures were evaluated, and the results showed that DMSO, NMP, and
toluene were less effective than DMF (entries 11ꢀ13). A low yield
was also found when the reaction was carried out at 60 °C, but
identical results were observed when the reaction was carried out at
80 or 100 °C (entries 14 and 15). The yield of 2a was reduced ob-
viously when using 5 mol % loading of CuI and 10 mol % of TMEDA
(entry 16).
The reaction of 1-bromo-2-(phenylethynyl)benzene (1a) with
Na2S was screened to optimize reaction conditions, and the results
are summarized in Table 1. Our investigation began with an
attempted annulation of substrate 1a with Na2S in DMF at 80 °C
in the absence of any catalyst; the desired product 2a could be
isolated only in 18% yield (entry 1). This result demonstrated that
high reaction temperature is essential in Takimiya’s procedure8 and
encouraged us to develop efficient catalytic systems. Subsequently, a
variety of copper salts were examined to optimize the reaction
conditions. The results displayed that both cuprous salts and cupric
With the optimal reaction conditions in hand, we explored the
scope of 2-bromo alkynylbenzenes for the thiolation annulation
reaction (Table 2). Initially, R substituents at the terminal alkyne
Received: May 31, 2011
Published: August 03, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201081v J. Org. Chem. 2011, 76, 7546–7550
|

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NOTE
Table 1. Screening Conditionsa
Table 2. CuI-Catalyzed Annulation of 2-Bromo Alkynylben-
zenes with Na2Sa
entry
[Cu]
ligand
solvent
T (°C)
yield (%)b
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
toluene
DMF
DMF
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
100
60
80
18
35
31
47
27
39
83
75
63
73
65
62
trace
82
54
67
CuCl
3
CuBr
CuI
4
5
Cu(OTf)2
Cu(OAc)2
CuI
6
7
TMEDA
1,10-phen
DMEDA
2,20-bipyridine
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
8
CuI
9
CuI
10
11
12
13
14
15
16c
CuI
CuI
CuI
CuI
CuI
CuI
CuI
a Reaction conditions: 1a (0.2 mmol), Na2S 9H2O (0.6 mmol), [Cu]
3
(10 mol %), and ligand (20 mol %) in solvent (2 mL) under N2
atmosphere for 24 h. b Isolated yield. c 5 mol % of CuI was added.
moiety of 2-(1-alkynyl)bromobenzene were evaluated (entries
1ꢀ14). The results demonstrated that both electron-deficient and
electron-rich phenyl group were compatible, but the reaction of
2-bromo alkynylbenzene bearing electron-deficient substituent pro-
vided a lower yield (entries 1ꢀ8). For example, substrates 1b and 1h,
bearing a 4-methylphenyl or 4-acetylphenyl group, underwent the
thiolation annulation with Na2S smoothly to afford the correspond-
ing benzo[b]thiophene in 80 and 50% yields, respectively (entries 1
and 7). We found that the steric effect of substituents affected the
reaction, and only trace product was detected when R was the bulky
(1,10-biphenyl)-2-yl group (entry 9). We were also pleased to find
that substrates bearing a heteroaryl group (such as pyridin-3-yl and
thiophen-2-yl) were tolerated very well to provide corresponding
product in good yields (entries 10 and 11). However, a low yield was
observed in the annulation reaction of substrate 1m or 1n, bearing a
TMS or CF3 group at the terminal of the triple bond (entries
12 and 13). Similarly, substrate 1o bearing an aliphatic alkyl
group did not work under the standard conditions (entry 14).
Subsequently, various multisubstituted 2-bromo alkynylben-
zenes were examined. The results displayed that the thiolation
reaction of 2-bromo alkynylbenzenes bearing a substituent
(such as methyl, Cl, and F atom) at the 4-position of the ben-
zene ring proceeded smoothly to afford product in good
yields. For example, substrates 1q and 1r, both bearing a
methyl at the 4-position of the bromobenzene moiety, were
treated with Na2S, CuI, and TMEDA to afford corresponding
product in 70 and 75% yields, respectively (entries 16 and 17).
All thiolation annulation reactions of 4-halo (Cl, F)-2-bromo
alkynylbenzenes with Na2S were conducted successfully. For
example, substrate 1u or 1v was reacted with Na2S under the
standard conditions to provide corresponding product in 84
and 74% yields, respectively (entries 20 and 21).
a Reaction conditions: 1 (0.2 mmol), Na2S 9H2O (0.6 mmol), CuI
3
(10 mol %), and TMEDA (20 mol %) in DMF (2 mL) at 80 °C under
N2 atmosphere for 24 h. b Isolated yield. c Detected by GCꢀMS.
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The Journal of Organic Chemistry
NOTE
Scheme 2
122.2, 118.8, 21.2; IR (neat, cmꢀ1) 2914, 1559, 1460, 1438, 809; LRMS
(EI, 70 eV) m/z (%) 224 (M+, 100), 189 (5), 178 (5), 112 (9).
2-m-Tolylbenzo[b]thiophene14 (2c): White solid (36.7 mg, 82%), mp
117.0ꢀ118.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H),
7.75 (d, J = 7.5 Hz, 1H), 7.52ꢀ7.51 (m, 3H), 7.35ꢀ7.29 (m, 3H), 7.15 (d,
J = 7.5 Hz, 1H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 144.4, 140.7,
139.5, 138.6, 134.2, 129.1, 128.8, 127.2, 124.4, 124.2, 123.7, 123.5, 122.2,
119.3, 21.4; IR (neat, cmꢀ1) 3052, 1604, 1486, 1454, 782; LRMS (EI, 70 eV)
m/z (%) 224 (M+, 100), 189 (5), 112 (9).
2-(4-Methoxyphenyl)benzo[b]thiophene13 (2d): White solid (34.1
mg, 71%), mp 191.3ꢀ193.5 °C; 1H NMR (500 MHz, CDCl3) δ7.81 (d, J=
8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.43 (s, 1H),
7.33ꢀ7.26 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 159.8, 144.1, 140.9, 139.2, 127.7, 127.1, 124.4, 123.9, 123.2,
122.2, 118.2, 114.4, 55.4; IR (neat, cmꢀ1) 2956, 1604, 1499, 1464, 1247,
1177, 1031, 820; LRMS (EI, 70 eV) m/z (%) 240 (M+, 100), 225 (69), 197
(39), 165 (20).
On the basis of the present results and the reported mechanism,9b
a possible mechanism was proposed as outlined in Scheme 2. Oxi-
dative addition of CuI to substrate 1 afforded intermediate A; the
following ligand exchange with sodium sulfide might provide inter-
mediate B, which could then undergo reductive elimination to form
intermediate C and regenerate CuI. The coordination of CuI with
intermediate C might provide copper complex D, subsequent addi-
tion to CꢀC triple bond gave intermediate E. Protonolysis of inter-
mediate E formed benzo[b]thiophenes 2 and regenerated the active
CuI. Study of the detailed mechanism is in progress.
2-(4-Chlorophenyl)benzo[b]thiophene15 (2e): White solid (40.0 mg,
82%), mp 190.5ꢀ192.1 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.0
Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.49 (s, 1H), 7.37
(d, J = 8.5 Hz, 2H), 7.33ꢀ7.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
142.8, 140.6, 139.5, 134.1, 132.8, 129.1, 127.6, 124.6, 124.5, 123.6, 122.3,
119.9; IR (neat, cmꢀ1) 3058, 1486, 1432, 1094, 1010, 815; LRMS (EI, 70
eV) m/z (%) 246 (M+, 39), 244 (M+, 100), 208 (19), 165 (17).
2-(4-(Trifluoromethyl)phenyl)benzo[b]thiophene13 (2f): White solid
1
(28.9 mg, 52%), mp 216.1ꢀ217.4 °C; H NMR (500 MHz, CDCl3) δ
7.85 (d, J = 7.5 Hz, 1H), 7.82ꢀ7.80 (m, 3H), 7.67 (d, J = 8.0 Hz, 2H), 7.63
(s, 1H), 7.40ꢀ7.34 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 142.3, 140.5,
139.9, 137.8, 130.1 (q, JCꢀF = 32.5 Hz), 126.6, 125.9 (q, JCꢀF = 3.8 Hz),
125.0, 124.8, 124.1 (q, JCꢀF = 270.3 Hz), 124.0, 122.4, 121.1; IR (neat,
cmꢀ1) 3068, 2933, 1611, 1599, 1454, 1322; LRMS (EI, 70 eV) m/z (%) 278
(M+, 100), 233 (8), 208 (10), 114 (14).
In conclusion, we have developed a practical CuI/TMEDA-
catalyzed thiolation annulation method for the synthesis of 2-sub-
stituted benzo[b]thiophenes. Inthe presence of CuI and TMEDA,
a variety of 2-bromo alkynylbenzene derivatives underwent
the annulation reaction with Na2S 9H2O at 80 °C to give the
3
corresponding benzo[b]thiophenes in moderate to good yields. In
contrast to harsh reaction conditions (ꢀ78 or 180 °C) of the
traditional methods,7,8 the mild reaction conditions of the present
procedure will be a new optional route for constructing the
benzo[b]thiophene ring.
2-(3-(Trifluoromethyl)phenyl)benzo[b]thiophene (2g): White solid
(30.1 mg, 54%), mp 102.6ꢀ105.3 °C; 1H NMR (500 MHz, CDCl3) δ
7.95 (s, 1H), 7.87ꢀ7.83 (m, 2H), 7.79 (d, J = 7.0 Hz, 1H), 7.61ꢀ7.58 (m,
2H), 7.56ꢀ7.52 (m, 1H), 7.40ꢀ7.33 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ142.3, 140.5, 139.7, 135.2, 131.5 (q, JCꢀF = 32.5 Hz), 129.6, 129.5,
124.9, 124.8, 124.7 (q, JCꢀF = 3.8 Hz), 124.0 (q, JCꢀF = 270.8 Hz), 123.9,
123.1 (q, JCꢀF = 3.8 Hz), 122.3, 120.7; IR (neat, cmꢀ1) 3058, 3039, 1607,
1521, 1456, 1438; LRMS (EI, 70 eV) m/z (%) 278 (M+, 100), 208 (9), 139
(10); HRMS (EI) calcd for C15H9F3S+ (M+) 278.0372, found 278.0382.
1-(4-(Benzo[b]thiophen-2-yl)phenyl)ethanone16 (2h): White solid
(25.2 mg, 50%), mp 165.2ꢀ166.7 °C; 1H NMR (500 MHz, CDCl3) δ
8.00 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 7.0 Hz, 1H), 7.81ꢀ7.78 (m, 3H), 7.66
(s, 1H), 7.39ꢀ7.33 (m, 2H), 2.62 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
197.3, 142.6, 140.4, 139.9, 138.7, 136.4, 129.1, 126.3, 125.0, 124.8, 124.0,
122.3, 121.2, 26.6; IR (neat, cmꢀ1) 3059, 1674, 1600, 1358, 1266, 819, 743;
LRMS (EI, 70 eV) m/z (%) 252 (M+, 82), 237 (100), 208 (39), 165 (40).
4-(Benzo[b]thiophen-2-yl)benzonitrile17 (2i): White solid (22.5 mg,
48%), mp 181.1ꢀ182.6 °C; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J =
7.5 Hz, 1H), 7.83ꢀ7.77 (m, 3H), 7.70 (d, J = 8.5 Hz, 2H), 7.66 (s, 1H),
7.42ꢀ7.34 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 141.6, 140.3,
140.0, 138.6, 132.7, 126.7, 125.3, 124.9, 124.1, 122.4, 121.8, 118.6, 111.4;
IR (neat, cmꢀ1) 2917, 2217, 1604, 1526, 1494, 1335, 822, 752; LRMS
(EI, 70 eV) m/z (%) 235 (M+, 100), 203 (10), 190 (15), 117 (8).
2-(Thiophen-2-yl)benzo[b]thiophene18 (2k): White solid (31.4 mg,
73%), mp 118.1ꢀ120.2 °C; 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.0
Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.40 (s, 1H), 7.30ꢀ7.28 (m, 2H),
7.08ꢀ7.05 (m, 2H), 7.03ꢀ7.01 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
140.4, 139.1, 137.4, 136.2, 127.9, 125.1, 124.7, 124.5, 124.3, 123.4, 122.1,
119.7; IR (neat, cmꢀ1) 3064, 1556, 1499, 1434, 1415, 815, 691; LRMS (EI,
70 eV) m/z (%) 216 (M+, 100), 184 (12), 171 (19), 108 (11).
’ EXPERIMENTAL SECTION
Typical Experimental Procedure for the CuI-Catalyzed
Thiolation Annulation Reaction. A mixture of 2-bromo alkynyl-
benzene 1(0.2 mmol), CuI (3.8 mg, 10 mol %), TMEDA (4.7 mg, 20 mol %),
and Na2S 9H2O (144 mg, 3 equiv) in DMF (2 mL) was evacuated and
3
backfilled with nitrogen (3 cycles) and then stirred at 80 °C until complete
consumption of starting material was indicated by TLC or GCꢀMS analysis.
After the reaction was completed, the mixture was filtered through a glass
filter and washed with ethyl acetate. The mixture was washed with brine and
extracted with ethyl acetate. The organic layers were dried with anhydrous
Na2SO4 and evaporated under vacuum, and the residue was purified by flash
column chromatography (hexane/ethyl acetate) to give product 2.
2-Phenylbenzo[b]thiophene8 (2a): White solid (34.8 mg, 83%), mp
172.2ꢀ173.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H),
7.76 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.54 (s, 1H), 7.43ꢀ7.40
(m, 2H), 7.36ꢀ7.27(m, 3H);13C NMR (125 MHz, CDCl3) δ144.2, 140.7,
139.5, 134.3, 128.9, 128.2, 126.5, 124.5, 124.3, 123.5, 122.3, 119.4; IR
(neat, cmꢀ1) 3051, 3023, 1487, 1457, 1429, 1335; LRMS (EI, 70
eV) m/z (%) 210 (M+, 100), 165 (21), 178 (12), 105 (13).
2-p-Tolylbenzo[b]thiophene13 (2b): White solid (35.8 mg, 80%), mp
166.1ꢀ168.2 °C; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H),
7.74 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.35ꢀ7.26
(m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 144.4, 140.8, 139.3, 138.3, 131.5, 129.6, 126.4, 124.4, 124.1, 123.4,
3-(Benzo[b]thiophen-2-yl)pyridine19 (2l): White solid (29.5 mg, 70%),
mp 131.2ꢀ132.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.57
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NOTE
(d, J= 4.5 Hz, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.85 (d, J= 7.5 Hz, 1H), 7.81 (d,
J = 7.5 Hz, 1H), 7.60 (s, 1H), 7.38ꢀ7.34 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 149.2, 147.5, 140.4, 140.2, 139.7, 133.5, 130.3, 124.9, 124.8,
123.8, 123.7, 122.3, 120.7; IR (neat, cmꢀ1) 3055, 1568, 1523, 1478, 1435,
1301,1192; LRMS (EI, 70 eV) m/z (%) 211 (M+, 100), 167 (12), 139 (17),
79 (9).
7.79ꢀ7.71 (m, 3H), 7.66 (d, J = 8.0 Hz, 2H), 7.56 (s, 1H), 7.51 (d, J = 8.5
Hz, 1H), 7.14ꢀ7.11 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 160.8 (d,
JCꢀF = 244.0 Hz), 142.0, 140.7 (d, JCꢀF = 10.0 Hz), 137.4, 136.9, 130.0 (q,
JCꢀF = 32.0 Hz), 126.4, 126.0 (q, JCꢀF = 4.0 Hz), 125.0 (d, JCꢀF = 9.0 Hz),
124.0 (q, JCꢀF = 270.4 Hz), 120.4, 113.9 (d, JCꢀF = 24.0 Hz), 108.5
(d, JCꢀF = 25.0 Hz); IR (neat, cmꢀ1) 3080, 1617, 1598, 1566, 1469; LRMS
(EI, 70 eV) m/z (%) 296 (M+, 100), 264 (8), 226 (8), 123 (12); HRMS
(EI) calcd for C15H8F4S+ (M+) 296.0277, found 296.0287.
Benzo[b]thiophene8 (2m): White solid (8.1 mg, 30%), mp 29.2ꢀ
31.0 °C.1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.5 Hz, 1H), 7.83
(d, J = 8.0 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 7.38ꢀ7.33 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 139.7, 139.6, 126.3, 124.2, 124.1, 123.8, 123.6, 122.5;
IR (neat, cmꢀ1) 3049, 1586, 1456, 1414, 1344, 795, 761; LRMS (EI, 70 eV)
m/z (%) 134 (M+, 100), 89 (11), 63 (6).
6-Chloro-2-phenylbenzo[b]thiophene22 (2v): White solid (36.0 mg,
74%), mp 192.6ꢀ194.8 °C; 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H),
7.69ꢀ7.66 (m, 3H), 7.49 (s, 1H), 7.44ꢀ7.41 (m, 2H), 7.37ꢀ7.34 (m, 1H),
7.31 (d, J = 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 144.9, 140.5,
139.1, 133.8, 130.3, 129.0, 128.5, 126.4, 125.3, 124.3, 121.8, 118.9; IR (neat,
cmꢀ1) 3023, 1520, 1445, 1099, 803; LRMS (EI, 70 eV) m/z (%) 246 (M+,
38), 244 (M+, 100), 208 (23), 165 (23).
2-(Trifluoromethyl)benzo[b]thiophene20 (2n): White solid (16.9 mg,
42%), mp 49.4ꢀ50.1 °C; 1H NMR (500 MHz, CDCl3) δ 7.89ꢀ7.86 (m,
2H), 7.69 (s, 1H), 7.48ꢀ7.42 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
140.2, 137.8, 131.3 (q, JCꢀF = 32 Hz) 126.6, 125.6 (q, JCꢀF = 4.0 Hz), 125.2,
125.1, 122.6, 122.5 (q, JCꢀF = 267.8 Hz); IR (neat, cmꢀ1) 1538, 1336, 1295,
1267, 1156; LRMS (EI, 70 eV) m/z(%) 202(M+, 100), 183 (33), 152 (28).
6-Methyl-2-phenylbenzo[b]thiophene21 (2p): White solid (33.6 mg,
75%), mp 145.0ꢀ147.4 °C; 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 7.5
Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.42ꢀ7.39 (m,
2H), 7.33ꢀ7.30 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 143.0, 139.8, 138.5, 134.3, 133.4, 128.9, 128.0, 126.3,
126.2, 123.2, 122.1, 119.2, 21.6; IR (neat, cmꢀ1) 3023, 2911, 1601, 1524,
1485, 1443, 840, 725; LRMS (EI, 70 eV) m/z (%) 224 (M+, 100), 189 (6),
147 (7), 112 (8).
’ ASSOCIATED CONTENT
Supporting Information. Copies of 1H and 13C NMR of
S
b
compounds 2aꢀ2v. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: zxg@wzu.edu.cn.
2-(4-Methoxyphenyl)-6-methylbenzo[b]thiophene (2q): White solid
1
(35.6 mg, 70%), mp 208.0ꢀ209.3 °C; H NMR (500 MHz, CDCl3) δ
’ ACKNOWLEDGMENT
7.63ꢀ7.60 (m, 4H), 7.37 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 9.0
Hz, 2H), 3.85 (s, 3H), 2.46 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.6,
142.9, 139.5, 138.7, 133.9, 127.6, 127.3, 126.1, 122.9, 122.0, 118.0, 114.3, 55.4,
21.6; IR (neat, cmꢀ1) 1604, 1529, 1497, 1255, 1177, 1032; LRMS (EI, 70
eV) m/z (%) 254 (M+, 100), 239 (67), 211 (27), 207 (38); HRMS (EI)
calcd for C16H14OS+ (M+) 254.0760, found 254.0764.
We thank the National Natural Science Foundation of China
(No. 21002070) and Zhejiang Provincial Natural Science Founda-
tion of China (No. Y4100307) for financial support.
’ REFERENCES
6-Methyl-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophene (2r): White
solid (43.8 mg, 75%), mp 184.3ꢀ186.1 °C; 1H NMR (500 MHz, CDCl3) δ
7.79 (d, J = 8.5 Hz, 1H), 7.69ꢀ7.64 (m, 3H), 7.61 (s, 1H), 7.57ꢀ7.53 (m,
2H), 7.19 (d, J = 8.0 Hz, 1H), 2.48 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
141.1, 140.2, 138.2, 138.0, 133.6, 129.3 (q, JCꢀF = 34.0 Hz), 126.4, 125.9 (q,
JCꢀF = 3.8 Hz), 124.1 (q, JCꢀF = 275.1 Hz), 123.6, 122.2, 120.8, 120.5, 21.6;
IR (neat, cmꢀ1) 2920, 2856, 1614, 1595, 1508, 1479; LRMS (EI, 70 eV) m/z
(%) 292 (M+, 100), 246 (8), 221 (11), 192 (6); HRMS (EI) calcd for
C14H10F3S+ (M+) 292.0528, found 292.0528.
(1) For selected recent examples, see: (a) Berrade, L.; Aisa, B.;
Ramirez, M.; Galiano, S.; Guccione, S.; Moltzau, L. R.; Levy, F. O.; Nicoletti,
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Chem. 2011, 54, 3086. (b) Venturelli, A.; Tondi, D.; Cancian, L.; Morandi, F.;
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Brancale, A.; Hamel, E. J. Med. Chem. 2007, 50, 2273. (d) Fournier dit
Chabert, J.; Marquez, B.; Neville, L.; Joucla, L.; Broussous, S.; Bouhours, P.;
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1999, 22, 1.
6-Fluoro-2-phenylbenzo[b]thiophene (2s): White solid (31.8 mg,
70%), mp 161.4ꢀ163.8 °C; 1H NMR (500 MHz, CDCl3) δ 7.71ꢀ7.67 (m,
3H), 7.52ꢀ7.49 (m, 2H), 7.44ꢀ7.41 (m, 2H), 7.36ꢀ7.33 (m, 1H),
7.12ꢀ7.08 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 160.5 (d, JCꢀF
=
242.5 Hz), 144.0, 140.4 (d, JCꢀF = 10.0 Hz), 137.2, 134.0, 129.0, 128.3, 126.4,
124.5 (d, JCꢀF = 9.0 Hz), 118.8, 113.5 (d, JCꢀF = 24.0 Hz), 108.4 (d, JCꢀF
=
25.0 Hz); IR (neat, cmꢀ1) 2972, 1713, 1598, 1566, 1468, 1251; LRMS (EI,
70 eV) m/z (%) 228 (M+, 100), 183 (18), 114 (12), 101 (6); HRMS (EI)
calcd for C14H9FS+ (M+) 228.0404, found 228.0405.
(3) (a) Qin, Z.; Kasrati, I.; Chandrasena, R. E. P.; Liu, H.; Yao, P.;
Petukhov, P. A.; Bolton, J. L.; Thatcher, G. R. J. J. Med. Chem. 2007, 50, 2682.
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6-Fluoro-2-p-tolylbenzo[b]thiophene (2t): White solid (32.9 mg,
68%), mp 198.4ꢀ200.2 °C; 1H NMR (500 MHz, CDCl3) δ 7.69ꢀ7.66 (m,
1H), 7.57 (d, J = 8.0 Hz, 2H), 7.50ꢀ7.48 (m, 1H), 7.44 (s, 1H), 7.23 (d, J =
8.0 Hz, 2H), 7.11ꢀ7.07 (m, 1H), 2.39 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 160.4 (d, JCꢀF = 242.6 Hz), 144.1, 140.2 (d, JCꢀF = 10.0 Hz),
138.3, 137.2, 131.2, 129.7, 126.2, 124.3 (d, JCꢀF = 9.0 Hz), 118.2, 113.4 (d,
JCꢀF = 24.0 Hz), 108.4 (d, JCꢀF = 25.0 Hz), 21.2; IR (neat, cmꢀ1) 3023,
2917, 1606, 1537, 1466, 1248, 850; LRMS (EI, 70 eV) m/z (%) 242 (M+,
100), 226 (5), 1976 (4), 121 (7); HRMS (EI) calcd for C15H11FS+ (M+)
242.0560, found 242.0561.
6-Fluoro-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophene (2u): White
(5) (a) Hsiao, C. N.; Kolasa, T. Tetrahedron Lett. 1992, 33, 2629.
(b) Mylari, B. L.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.;
solid (49.6 mg, 84%), mp 163.2ꢀ164.0 °C; 1H NMR (500 MHz, CDCl3) δ
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