Halocyclization of 2-alkynylthioanisoles by cupric halides: synthesis of 2-substituted 3-halobenzo[b]thiophenes

Article abstract of DOI:10.1016/j.tet.2006.10.068

Reaction of 2-alkynylthioanisoles 3 with 2 equiv of CuX₂ (X=Br or Cl) in refluxing CH₃CN for 2.5 h gave the 2-substituted 3-halobenzo[b]thiophenes 4 in good yields.

Full text of DOI:10.1016/j.tet.2006.10.068

Tetrahedron 63 (2007) 356–362
Halocyclization of 2-alkynylthioanisoles by cupric halides:
synthesis of 2-substituted 3-halobenzo[b]thiophenes
Wen-Der Lub and Ming-Jung Wua,
*
aFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan
bGraduate Institute of Pharmaceutical Science, Kaohsiung Medical University, Kaohsiung, Taiwan
Received 25 August 2006; revised 24 October 2006; accepted 25 October 2006
Available online 14 November 2006
Abstract—Reaction of 2-alkynylthioanisoles 3 with 2 equiv of CuX2 (X¼Br or Cl) in refluxing CH3CN for 2.5 h gave the 2-substituted
3-halobenzo[b]thiophenes 4 in good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
catalyst. The first attempt for the halocyclization was carried
out by treatment of 2-phenylethynylthioanisole (3a) with
2 equiv of CuCl2 in CH3CN at room temperature for 18 h.
2-Phenyl-3-chlorobenzo[b]thiophene (4aa) was obtained in
65% yield. When the reaction was carried out under reflux-
ing temperature of acetonitrile, the reaction time could be
reduced to 2.5 h and the isolated yield of compound 4aa
increased to 71%. On the other hand, treatment of CuBr2
with 3a under the same reaction conditions gave 4ab in
76% yield. CuF2 has also been tested for the halocyclization
of 3a and no product was formed even after stirring for 48 h.
After finding that CuCl2 and CuBr2 are effective reagents
for the halocyclization of 2-phenylethynylthioanisole (3a),
we turned our attention to explore the generality of this
cyclization reaction. Thus, various 2-(2-substituted ethynyl)-
thioanisoles 3b–l were carried out for the halocyclization
reactions. The results are summarized in Table 1.
The benzo[b]thiophenes have attracted much attention as the
synthetic target molecules due to the wide spectrum of bio-
logical activities. These compounds often exhibit as potent
antimitotic,1 antipsychotic,2 and antiinflammatory3 agents or
herpes virus inhibitors.4 For instance, Arzoxifene (1) and
Raloxifene (2) were found to be the unique selective estro-
gen receptor modulators (SERMs) and antitubulin agents.5,6
To synthesize these biological active compounds, the 2-sub-
stituted 3-halobenzo[b]thiophenes appear to be the key syn-
thetic intermediates. Although the efficient synthesis of the
iodo and bromo derivatives has recently been reported by
Flynn7 and Larock,8 no chlorinating agent was described
in these papers. We herein wish to report an efficient method
to prepare the 2-substituted 3-chlorobenzo[b]thiophenes as
well as the bromo analogs using commercially available
copper halides as the promotors.
From the results, we can see that all reactions work well
under the optimized conditions. The aryl group bearing
either the electron-donating or withdrawing group on the
phenyl ring has little effect on the cyclization reaction
(entries 3–6). It also works well when the substituent at the
terminus alkyne is pyrrole or thiophene ring (entries 7 and
8). The alkyl substituent at the terminus alkyne also provided
the 3-halobenzo[b]thiophenes in good yields. Only when the
substituent is tert-butyl group, the reaction of 3k with CuBr2
gave the cyclization product 4kb in 57% yield along with
25% of the bromine addition adduct 5kb.10 A similar result
was also found by reaction of o-(2-trimethylsilylethynyl)-
thioanisole (3l) with CuBr2. The cyclization product 4lb
and the desilylated adduct 6lb11 were isolated in 10% and
26% yields, respectively. A majority (45%) of the bromine
addition adduct 5lb was obtained (Eq. 1). The structure of
5lb was unambiguously determined by single crystal X-ray
analysis12 as shown in Figure 1.
O
N
X
R
S
X = O, R = OMe: Arzoxifene (1)
X = CO, R = OH: Raloxifene (2)
2. Results and discussion
The precursors, 2-alkynylthioanisoles (3a–l), were prepared
from the 2-iodothioanisole by the Sonogashira coupling
reaction9 with terminal alkynes using Pd(PPh3)4 as the
* Corresponding author. Tel.: +886 7 3121101x2220; fax: +886 7 3125339;
e-mail: mijuwu@kmu.edu.tw
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.068

W.-D. Lu, M.-J. Wu / Tetrahedron 63 (2007) 356–362
357
Table 1. CuX2 promoted cyclization of 2-alkynylthioanisoles
It was reported that cupric bromide in refluxing acetonitrile
would produce bromine and cupric chloride is not prone to
decomposition to generate chlorine at that temperature.13
A plausible mechanism for the chlorocyclization reaction
is shown in Scheme 1. First of all, the cupric chloride forms
a 1:1 complex with 3 followed by anti attack of the sulfur on
the thiomethyl group to the alkyne to give the sulfonium salt
7. Finally, removal of the methyl group by chloride via SN2
displacement would give the 3-chlorobenzo[b]thiophenes 4.
However, the formation of 2-substituted 3-bromobenzo[b]-
thiophenes could either proceed as the same reaction mech-
anism as above or by bromine promoted pathway reported
by Larock.8
R
X
CuX2
R
CH3CN, temp, time
S
SMe
3
4
R
Temp
Time (h)
Products, yieldsa (%)
3a, R¼C6H5
rt
18
4aa, 65
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
4aa, 71 (4ab, 76)
4ba, 71 (4bb, 87)
4ca, 81 (4cb, 81)
4da, 75 (4db, 79)
4ea, 99 (4eb, 99)
4fa, 78 (4fb, 82)
4ga, 90 (4gb, 90)
4ha, 87 (4hb, 80)
4ia, 75 (4ib, 78)
4ja, 71 (4jb, 79)
4ka, 87
3b, R¼4-MeOC6H4
3c, R¼4-HOC6H4
3d, R¼4-MeC6H4
3e, R¼4-CNC6H4
3f, R¼3-(C5H4)N
3g, R¼2-(C4H3)S
3h, R¼(CH2)5CH3
3i, R¼(CH2)4OH
3j, R¼CH2CH(CH3)2
3k, R¼t-Bu
X
Cu
R
X
R
X
3l, R¼SiMe3
4la, 71
CuX2
R
a
CH3
The numbers in parentheses are yields of the bromination products.
S
S
S
CH3
CH3
7
3
X
Cu
X
X
R
S
4
Scheme 1.
To explore the synthetic utility of these halobenzo[b]thio-
phenes, one of the cyclization product, 2-(4-methylphenyl)-
3-bromobenzo[b]thiophene (4ib), was converted to the
2,3-diarylbenzo[b]thiophene 814 by Suzuki cross-coupling
reaction with phenylboronic acid in 68% yield (Eq. 2).
Br
Ph
PhB(OH)2
Pd(PPh3)4
CH3
CH3
ð2Þ
CuI, Na2CO3,
Benzene,
reflux 6h
S
S
8, 68%
4db
In conclusion, we have demonstrated that cupric bromide
and cupric chloride are efficient halocyclization agents of
2-alkynylthioanisoles. These cyclization reactions gave the
2-substituted 3-halobenzo[b]thiophenes in good yields.
3. Experimental section
Figure 1. ORTEP plots for X-ray crystal structures of 5lb.
3.1. Typical procedure for Sonogashira coupling
reaction of 1-octyne with 2-iodothioanisole
Br
R
Br
Br
CuBr2
Method A: 1-octyne (3.2 mmol), 2-iodothioanisole (3.2
mmol), Pd(PPh3)4 (5 mol %), CuI (2 mol %), and n-BuNH2
(1.5 mmol) in ether (20 mL) were stirred at room tempera-
ture for 4 h. The saturated aqueous solutions of NH4Cl and
NaHCO3 were added subsequently into the reaction mixture
and extracted with EtOAc. The combined organic extracts
were dried over anhydrous MgSO4(s). After filtration and
removal of solvent, the residue was purified by column
chromatography to give the products.
R
+
CH3CN
Reflux, 2.5h
R
S
SCH3
SCH3
4kb, R = tBu, 10%
5kb, R = tBu, 45%
5lb, R = SiMe3, 25 %
3k, R = tBu
3l, R = SiMe3
ð1Þ
4lb, R = SiMe3, 57 %
Br
H
S
6lb, 26 %

358
W.-D. Lu, M.-J. Wu / Tetrahedron 63 (2007) 356–362
3.2. Typical procedure for the halocyclization of
2-phenyl-3-chlorobenzo[b]thiophene
1.2 Hz, 1H), 7.35 (td, J¼7.6, 1.2 Hz, 1H), 7.20 (d,
J¼7.6 Hz, 1H), 7.18 (td, J¼7.2, 1.2 Hz, 1H), 2.51 (s, 3H);
13C NMR (100 MHz, CDCl3): d 142.2, 132.4, 131.9,
131.8, 131.7, 131.6, 129.5, 128.0, 124.2, 124.0, 120.0,
118.5, 111.4, 93.9, 91.1, 14.9; MS (70 eV) m/z (%): 249
(100) [M+], 233 (13), 190 (12), 147 (42); HMRS (EI) calcd
for C16H11NS 249.0612, found 249.0613; Anal. Calcd for
C16H11NS: C, 77.07; H, 4.45; S, 12.86; N, 5.62. Found: C,
77.22; H, 4.45; S, 12.98; N, 5.63.
Method B: to a stirred solution of 2-alkynylthioanisole
(1 mmol) in CH3CN (5 mL) was added CuCl2 (2 mmol) or
CuBr2 (2 mmol), the solution was heated to reflux and stirred
at this temperature for 2.5 h. After cooling to room temper-
ature, the saturated aqueous solution of NH4Cl was added
subsequently into the reaction mixture and extracted with
EtOAc. The combined organic extracts were dried over
anhydrous MgSO4(s). After filtration and removal of sol-
vent, the residue was purified by column chromatography
to give the products.
3.2.6. o-(3-Pyridinylethynyl)thioanisole (3f). Obtained as
a brown oil; H NMR (400 MHz, CDCl3): d 8.81 (br s,
1
1H), 8.56 (br s, 1H), 7.88 (dt, J¼8.0, 2.0 Hz, 1H), 7.50
(dd, J¼7.6, 1.6 Hz, 1H), 7.36 (d, J¼8.0 Hz, 1H), 7.33–
7.29 (m, 1H), 7.20 (d, J¼8.0 Hz, 1H), 7.14 (t, J¼7.6 Hz,
1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3): d 151.8,
148.2, 141.9, 138.6, 132.3, 129.3, 129.3, 124.2, 124.0,
123.1, 120.3, 92.0, 90.2, 15.0; MS (70 eV) m/z (%): 225
(100) [M+], 224 (68), 223 (18), 147 (30), 139 (10); HMRS
(EI) calcd for C14H11NS 225.0612, found 225.0616.
3.2.1. o-(Phenylethynyl)thioanisole (3a). Obtained as a
yellow oil; H NMR (400 MHz, CDCl3): d 7.60–7.50 (m,
1
2H), 7.48 (d, J¼1.2 Hz, 1H), 7.38–7.28 (m, 4H), 7.19
(d, J¼6.8 Hz, 1H), 7.12 (t, J¼6.4 Hz, 1H), 2.52 (s, 3H);
13C NMR (100 MHz, CDCl3): d 141.6, 132.2, 131.5,
128.7, 128.4, 128.3, 126.0, 124.2, 124.1, 121.3, 113.6,
95.8, 86.8, 15.0; MS (70 eV) m/z (%): 224 (100) [M+], 223
(75), 221 (13), 208 (19), 147 (16); HMRS (EI) calcd for
C15H12S 224.0660, found 224.0657.
3.2.7. o-(2-Thienylethynyl)thioanisole (3g). Obtained as
a brown oil; 1H NMR (400 MHz, CDCl3): d 7.46 (dd,
J¼7.6, 1.6 Hz, 1H), 7.32–7.28 (m, 3H), 7.19 (d, J¼7.6 Hz,
1H), 7.11 (td, J¼6.4, 1.2 Hz, 1H), 7.03 (dd, J¼5.2, 1.6 Hz,
1H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3): d 141.5,
132.1, 132.0, 128.8, 128.8, 127.5, 127.1, 124.2, 124.1,
121.0, 90.4, 88.9, 15.1; MS (70 eV) m/z (%): 230 (23)
[M+], 229 (100), 228 (86), 197 (16), 171 (19); HMRS (EI)
calcd for C13H10S2 230.0224, found 230.0222.
3.2.2. o-(4-Methoxyphenylethynyl)thioanisole (3b). Ob-
tained as an orange solid; mp 59–60 ꢀC; 1H NMR
(400 MHz, CDCl3): d 7.52 (dd, J¼9.2, 2.4 Hz, 2H), 7.47
(dd, J¼8.8, 2.0 Hz, 1H), 7.28 (t, J¼7.6 Hz, 1H), 7.17 (d,
J¼8.0 Hz, 1H), 7.12 (t, J¼7.6 Hz, 1H), 6.89 (dd, J¼8.8,
2.0 Hz, 2H), 3.83 (s, 3H), 2.50 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 141.6, 134.2, 133.3, 132.2, 128.6,
127.5, 124.4, 124.2, 118.3, 115.5, 114.2, 113.9, 96.1, 85.8,
55.5, 55.4; MS (70 eV) m/z (%): 254 (90) [M+], 253 (63),
247 (51), 223 (16), 195 (14), 147 (19); HMRS (EI) calcd
for C16H14OS 254.0765, found 254.0775; Anal. Calcd for
C16H14OS: C, 75.55; H, 5.55; S, 12.61. Found: C, 75.79;
H, 5.71; S, 11.39.
3.2.8. o-(1-Octynyl)thioanisole (3h). Obtained as an orange
oil; 1H NMR (400 MHz, CDCl3): d 7.36 (dd, J¼7.6, 1.2 Hz,
1H), 7.34 (td, J¼8.0, 0.4 Hz, 1H), 7.12 (d, J¼7.6 Hz, 1H),
7.05 (t, J¼7.2 Hz, 1H), 2.49 (t, J¼7.2 Hz, 2H), 2.47 (s,
3H), 1.68–1.61 (m, 2H), 1.59–1.48 (m, 2H), 1.34–1.31 (m,
4H), 0.93–0.83 (m, 3H); 13C NMR (100 MHz, CDCl3):
d 141.1, 132.2, 127.9, 124.0, 123.7, 122.0, 97.4, 78.0,
31.3, 28.6, 28.5, 22.5, 19.6, 14.9, 14.1; MS (70 eV) m/z
(%): 232 (39) [M+], 217 (100), 173 (11), 162 (14), 147
(74), 115 (17); HMRS (EI) calcd for C15H20S 232.1286,
found 232.1292.
3.2.3. o-(4-Hydroxyphenylethynyl)thioanisole (3c). Ob-
tained as a brown oil; 1H NMR (400 MHz, CDCl3):
d 7.48–7.44 (m, 3H), 7.30 (t, J¼8.0 Hz, 1H), 7.17 (d,
J¼6.8 Hz, 3H), 7.12 (t, J¼7.6 Hz, 1H), 6.82 (d, J¼8.8 Hz,
3H), 5.81 (br s, 1H), 2.50 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 156.1, 141.2, 133.2, 131.9, 128.4, 124.2, 124.0,
121.6, 115.5, 115.5, 115.5, 115.2, 95.9, 85.5, 15.1; MS
(70 eV) m/z (%): 240 (35) [M+], 226 (100), 197 (10), 165
(11); HMRS (EI) calcd for C15H12OS 240.0609, found
240.0606.
3.2.9. o-(1-Hydroxyhexynyl)thioanisole (3i). Obtained as a
yellow oil; 1H NMR (400 MHz, CDCl3): d 7.34 (dd, J¼6.0,
1.6 Hz, 1H), 7.24 (td, J¼6.4, 1.6 Hz, 1H), 7.12 (dd, J¼7.2,
0.8 Hz, 1H), 7.04 (td, J¼6.4, 1.2 Hz, 1H), 3.72 (t,
J¼6.4 Hz, 2H), 2.54 (t, J¼6.4 Hz, 2H), 2.46 (s, 3H), 1.83–
1.57 (m, 4H), 1.45 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 141.0, 132.2, 128.1, 124.1, 123.7, 121.8, 96.8,
78.4, 62.4, 31.8, 24.8, 19.4, 14.9; MS (70 eV) m/z (%):
220 (25) [M+], 205 (13), 187 (76), 172 (19), 161 (31), 147
(100); HMRS (EI) calcd for C13H16OS 220.0922, found
220.0926.
3.2.4. o-(4-Methylphenylethynyl)thioanisole (3d). Ob-
tained as a yellow oil; 1H NMR (400 MHz, CDCl3):
d 7.52–7.49 (m, 3H), 7.33 (t, J¼8.4 Hz, 1H), 7.19–7.17
(m, 3H), 7.14 (t, J¼7.6 Hz, 1H), 2.52 (s, 3H), 2.39 (s, 3H);
13C NMR (100 MHz, CDCl3): d 141.5, 138.4, 132.0,
131.4, 131.4, 129.0, 129.0, 128.5, 124.1, 124.0, 121.4,
120.0, 96.0, 86.2, 21.4, 14.9; MS (70 eV) m/z (%): 238
(100) [M+], 237 (71), 223 (20), 221 (29), 208 (10), 147
(23); HMRS (EI) calcd for C16H14S 238.0816, found
238.0823.
3.2.10. o-(4-Methyl-1-pentynyl)thioanisole (3j). Obtained
as an orange oil; H NMR (400 MHz, CDCl3): d 7.37 (d,
1
J¼8.0 Hz, 1H), 7.26 (t, J¼7.6 Hz, 1H), 7.12 (d, J¼7.6 Hz,
1H), 7.04 (t, J¼7.6 Hz, 1H), 2.47 (s, 3H), 2.39 (d,
J¼6.4 Hz, 2H), 1.97 (q, 1H), 1.08 (d, J¼6.8 Hz, 3H), 1.07
(d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 141.1,
132.2, 127.9, 124.0, 123.6, 122.0, 96.3, 78.9, 28.8, 28.2,
22.0, 22.0, 14.9; MS (70 eV) m/z (%): 204 (17) [M+], 153
3.2.5. o-(4-Cyanophenylethynyl)thioanisole (3e). Ob-
tained as a white solid; mp 66–67 ꢀC; 1H NMR (400 MHz,
CDCl3): d 7.63 (d, J¼0.4 Hz, 4H), 7.47 (dd, J¼7.6,

W.-D. Lu, M.-J. Wu / Tetrahedron 63 (2007) 356–362
359
(8), 148 (9), 127 (7); HMRS (EI) calcd for C13H16S
204.0973, found 204.0974.
J¼6.8 Hz, 1H), 7.40 (t, J¼6.8 Hz, 1H), 7.02 (dt, J¼9.2,
2.4 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 160.0, 139.2, 138.1, 137.4, 130.9, 130.7, 125.3, 125.2,
125.1, 123.4, 122.0, 114.1, 114.0, 104.2, 55.3; MS (70 eV)
m/z (%): 317 (96) [M+], 305 (32), 303 (31), 277 (17), 195
(25), 152 (22); HMRS (EI) calcd for C15H11BrOS
317.9714, found 317.9706. Anal. Calcd for C15H11BrOS:
C, 56.44; H, 3.47; S, 10.04. Found: C, 56.22; H, 3.69;
S, 9.85.
3.2.11. o-(tert-Butylethynyl)thioanisole (3k). Obtained as a
yellow oil; 1H NMR (400 MHz, CDCl3): d 7.34 (dd, J¼6.0,
1.2 Hz, 1H), 7.23 (td, J¼6.4, 1.6 Hz, 1H), 7.11 (d, J¼7.6 Hz,
1H), 7.04 (td, J¼6.0, 1.6 Hz, 1H), 2.46 (s, 3H), 1.36 (s, 9H);
13C NMR (100 MHz, CDCl3): d 141.2, 131.9, 127.9, 123.9,
123.6, 121.9, 105.5, 31.1, 30.9, 30.6, 30.3, 28.3, 14.8; MS
(70 eV) m/z (%): 204 (19) [M+], 197 (27), 149 (100), 119
(10), 111 (15); HMRS (EI) calcd for C13H16S 204.0973,
found 204.0972.
3.2.17. 2-(4-Hydroxyphenyl)-3-chlorobenzo[b]thiophene
(4ca). Obtained as a yellow solid, mp 144–145 ꢀC; 1H
NMR (400 MHz, CDCl3): d 7.85 (d, J¼8.0 Hz, 1H), 7.80
(d, J¼8.4 Hz, 1H), 7.70 (dd, J¼6.8, 2.4 Hz, 1H), 7.48 (t,
J¼7.2 Hz, 1H), 7.40 (t, J¼6.4 Hz, 1H), 6.96 (dd, J¼6.8,
2.4 Hz, 2H), 5.21 (br s, 1H), 2.50 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 156.0, 137.8, 136.3, 136.1, 130.7,
130.7, 125.2, 124.9, 124.8, 122.1, 122.0, 115.7, 115.6,
115.6; Anal. Calcd for C14H9ClOS: C, 64.49; H, 3.48; S,
12.28. Found: C, 64.52; H, 3.53; S, 11.59.
3.2.12. o-(Trimethylsilylethynyl)thioanisole (3l). Obtained
as a yellow oil; H NMR (400 MHz, CDCl3): d 7.40 (dd,
1
J¼7.6, 0.4 Hz, 1H), 7.27 (td, J¼6.8, 2.0 Hz, 1H), 7.13 (d,
J¼8.0 Hz, 1H), 7.05 (td, J¼8.8, 1.6 Hz, 1H), 2.47 (s, 3H),
0.27 (s, 9H); 13C NMR (100 MHz, CDCl3): d 141.9, 132.6,
128.9, 124.0, 123.9, 121.1, 102.0, 101.3, 14.9, ꢁ0.06 (3C);
MS (70 eV) m/z (%): 220 (77) [M+], 215 (15), 251 (19),
205 (78), 177 (30), 115 (100); HMRS (EI) calcd for
C12H16SSi 220.0742, found 220.0749.
3.2.18. 2-(4-Hydroxyphenyl)-3-bromobenzo[b]thiophene
(4cb). Obtained as a yellow solid, mp 125–126 ꢀC; 1H
NMR (400 MHz, CDCl3): d 7.85 (d, J¼8.0 Hz, 1H), 7.80
(d, J¼8.4 Hz, 1H), 7.66 (dd, J¼6.8, 2.4 Hz, 2H), 7.48 (t,
J¼6.8 Hz, 1H), 7.40 (t, J¼6.8 Hz, 1H), 6.96 (dd, J¼6.8,
2.0 Hz, 2H), 5.81 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 156.3, 139.1, 138.1, 137.3, 131.0, 131.0, 125.3,
125.2, 125.1, 123.4, 122.0, 115.5, 115.5, 104.1; Anal. Calcd
for C14H9BrOS: C, 55.10; H, 2.97; S, 10.51. Found: C,
55.49; H, 3.08; S, 10.16.
3.2.13. 2-Phenyl-3-chlorobenzo[b]thiophene (4aa). Ob-
tained as a white solid, mp 64–65 ꢀC; 1H NMR (400 MHz,
CDCl3): d 7.88 (d, J¼7.2 Hz, 1H), 7.87–7.79 (m, 3H),
7.51–7.40 (m, 5H); 13C NMR (100 MHz, CDCl3): d 137.7,
136.7, 136.2, 132.3, 129.2, 129.1, 128.6, 128.5, 125.4,
125.3, 125.0, 122.3, 122.2, 116.3; MS (70 eV) m/z (%):
244 (100) [M+], 212 (2), 208 (21), 165 (20), 139 (4);
HMRS (EI) calcd for C14H9ClS 244.0113, found
244.0107; Anal. Calcd for C14H9ClS: C, 68.72; H, 3.71; S,
13.10. Found: C, 68.68; H, 3.68; S, 13.09.
3.2.19. 2-(4-Methylphenyl)-3-chlorobenzo[b]thiophene
1
(4da). Obtained as a white solid, mp 78–79 ꢀC; H NMR
3.2.14. 2-Phenyl-3-bromobenzo[b]thiophene (4ab). Ob-
tained as a white solid, mp 62–63 ꢀC; 1H NMR (400 MHz,
CDCl3): d 7.89 (d, J¼7.2 Hz, 1H), 7.81 (d, J¼8.0 Hz, 1H),
7.78–7.76 (m, 2H), 7.51–7.39 (m, 5H); 13C NMR
(100 MHz, CDCl3): d 139.1, 138.2, 137.6, 133.0, 129.6,
129.5, 128.7, 128.5, 128.4, 125.4, 125.2, 123.6, 122.1,
104.9; MS (70 eV) m/z (%): 287 (97) [M+], 208 (44), 165
(36), 163 (11), 145 (10), 104 (16); HMRS (EI) calcd for
C14H9BrS 287.9608, found 287.9607; Anal. Calcd for
C14H9BrS: C, 58.15; H, 3.14; S, 11.09. Found: C, 58.16;
H, 3.06; S, 11.14.
(400 MHz, CDCl3): d 7.89 (d, J¼7.2 Hz, 1H), 7.82 (d,
J¼8.0 Hz, 1H), 7.72 (d, J¼8.0 Hz, 2H), 7.48 (t, J¼8.4 Hz,
1H), 7.42 (t, J¼6.8 Hz, 1H), 7.39 (d, J¼8.0 Hz, 2H), 2.43
(s, 3H); 13C NMR (100 MHz, CDCl3): d 138.7, 137.8,
136.5, 136.4, 129.4, 129.3, 129.3, 129.0, 129.0, 125.2,
124.9, 122.2, 122.0, 116.2, 21.3; Anal. Calcd for
C15H11ClS: C, 69.62; H, 4.28; S, 12.39. Found: C, 69.68;
H, 4.36; S, 11.70.
3.2.20. 2-(4-Methylphenyl)-3-bromobenzo[b]thiophene
1
(4db). Obtained as a white solid, mp 63–64 ꢀC; H NMR
(400 MHz, CDCl3): d 7.87 (d, J¼8.0 Hz, 1H), 7.81 (d,
J¼8.0 Hz, 1H), 7.67 (d, J¼8.4 Hz, 2H), 7.49 (t, J¼7.2 Hz,
1H), 7.41 (t, J¼8.4 Hz, 1H), 7.30 (d, J¼7.6 Hz, 2H), 2.43
(s, 3H); 13C NMR (100 MHz, CDCl3): d 139.1, 138.8,
138.3, 137.5, 130.1, 129.4, 129.4, 129.3, 129.3, 125.3,
125.1, 123.5, 122.1, 104.5, 21.3; Anal. Calcd for
C15H11BrS: C, 59.42; H, 3.66; S, 10.57. Found: C, 59.59;
H, 3.68; S, 10.46.
3.2.15. 2-(4-Methoxyphenyl)-3-chlorobenzo[b]thiophene
(4ba). Obtained as a yellow solid, mp 102–103 ꢀC; 1H
NMR (400 MHz, CDCl3): d 7.87 (d, J¼7.2 Hz, 1H), 7.78
(d, J¼7.2 Hz, 1H), 7.74 (d, J¼8.8 Hz, 2H), 7.47 (dt,
J¼7.2, 0.8 Hz, 1H), 7.41 (dt, J¼6.8, 1.2 Hz, 1H), 7.03 (d,
J¼8.8 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 159.9, 137.8, 136.3, 136.2, 130.5, 130.4, 130.3,
125.1, 124.9, 124.6, 122.1, 121.9, 114.1, 114.0, 55.2; MS
(70 eV) m/z (%): 274 (100) [M+], 261 (17), 259 (43), 231
(32), 195 (16), 152 (14); HMRS (EI) calcd for C15H11ClOS
274.0219, found 274.0214; Anal. Calcd for C15H11ClOS: C,
65.57; H, 4.04; S, 11.67. Found: C, 65.53; H, 4.02; S, 11.64.
3.2.21. 2-(4-Cyanophenyl)-3-chlorobenzo[b]thiophene
(4ea). Obtained as a white solid, mp 126–127 ꢀC; 1H NMR
(400 MHz, CDCl3): d 7.93–7.89 (m, 1H), 7.91 (d,
J¼8.0 Hz, 2H), 7.82 (d, J¼8.0 Hz, 1H), 7.77 (d, J¼8.0 Hz,
2H), 7.51 (t, J¼7.0 Hz, 1H), 7.46 (t, J¼6.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 137.5, 136.9, 132.3,
132.1, 132.0, 130.8, 129.7, 129.5, 128.7, 126.3, 125.4,
122.6, 122.3, 118.5, 112.0; MS (70 eV) m/z (%): 269 (100)
[M+], 233 (14), 207 (1), 239 (46), 190 (19), 117 (4);
3.2.16. 2-(4-Methoxyphenyl)-3-bromobenzo[b]thiophene
1
(4bb). Obtained as a yellow solid, mp 83–84 ꢀC; H NMR
(400 MHz, CDCl3): d 7.86 (d, J¼7.6 Hz, 1H), 7.80 (d,
J¼7.6 Hz, 1H), 7.72 (dt, J¼8.8, 2.8 Hz, 2H), 7.46 (t,

360
W.-D. Lu, M.-J. Wu / Tetrahedron 63 (2007) 356–362
HMRS (EI) calcd for C15H8ClNS 269.0066, found
269.0064; Anal. Calcd for C15H8ClNS: C, 66.79; H, 2.99;
S, 11.89; N, 5.19. Found: C, 66.49; H, 2.92; S, 11.89; N, 5.19.
J¼7.2 Hz, 2H), 1.43–1.26 (m, 6H), 0.89 (t, J¼6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 139.0, 136.9, 136.3,
124.6, 124.5, 122.3, 121.2, 117.7, 31.5, 30.2, 28.7, 28.2,
22.5, 14.0; MS (70 eV) m/z (%): 252 (27) [M+], 183 (27),
181 (100), 149 (12), 147 (27); HMRS (EI) calcd for
C14H17ClS 252.0739, found 252.0739.
3.2.22. 2-(4-Cyanophenyl)-3-bromobenzo[b]thiophene
(4eb). Obtained as a white solid, mp 141–142 ꢀC; 1H NMR
(400 MHz, CDCl3): d 7.91–7.85 (m, 1H), 7.90 (d, J¼
8.4 Hz, 2H), 7.85 (dd, J¼8.0, 0.8 Hz, 1H), 7.77 (dt, J¼8.0,
0.4 Hz, 2H), 7.51 (td, J¼7.6, 0.8 Hz, 2H), 7.46 (t,
J¼6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 138.9,
137.8, 137.7, 135.7, 132.3, 132.2, 130.2, 130.1, 126.2,
125.6, 124.0, 122.2, 118.4, 112.2, 106.7; MS (70 eV) m/z
(%): 312 (97) [M+], 235 (25), 233 (39), 207 (6), 190 (76),
188 (16); HMRS (EI) calcd for C15H8BrNS 312.9561,
found 312.9562; Anal. Calcd for C15H8BrNS: C, 57.34;
H, 2.57; S, 10.21; N, 4.46. Found: C, 57.79; H, 2.87; S,
9.82; N, 4.24.
3.2.28. 2-Hexyl-3-bromobenzo[b]thiophene (4hb). Ob-
tained as a yellow oil; 1H NMR (400 MHz, CDCl3): d 7.75
(dt, J¼8.0, 3.6 Hz, 2H), 7.45 (td, J¼8.0, 0.8 Hz, 1H), 7.33
(td, J¼8.4, 0.8 Hz, 1H), 2.94 (t, J¼7.6 Hz, 2H), 1.73 (q,
J¼7.6 Hz, 2H), 1.57–1.26 (m, 6H), 0.90 (t, J¼6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 140.9, 138.3, 137.0,
124.8, 124.6, 122.5, 122.2, 105.6, 31.5, 30.2, 29.9, 28.7,
22.5, 14.0; MS (70 eV) m/z (%): 296 (45) [M+], 227 (57),
226 (41), 224 (91), 225 (13), 147 (100); HMRS (EI) calcd
for C14H17BrS 296.0234, found 296.0241.
3.2.23. 2-(3-Pyridinyl)-3-chlorobenzo[b]thiophene (4fa).
Obtained as a white solid, mp 73–74 ꢀC; 1H NMR
(400 MHz, CDCl3): d 9.02 (br s, 1H), 8.64 (br s, 1H), 8.11
(d, J¼8.0 Hz, 1H), 7.88 (d, J¼7.2 Hz, 1H), 7.82 (d,
J¼7.6 Hz, 1H), 7.50–7.40 (m, 3H); 13C NMR (100 MHz,
CDCl3): d 149.5, 149.2, 137.4, 136.8, 136.4, 132.2, 128.8,
125.9, 125.3, 123.4, 122.4, 122.3, 118.1; Anal. Calcd for
C13H8ClNS: C, 63.54; H, 3.28; S, 13.01; N, 5.07. Found:
C, 63.74; H, 3.44; S, 12.59; N, 5.63.
3.2.29. 2-Hydroxybutyl-3-chlorobenzo[b]thiophene (4ia).
Obtained as a yellow oil; H NMR (400 MHz, CDCl3):
1
d 7.75 (dd, J¼8.4, 0.4 Hz, 2H), 7.41 (td, J¼8.0, 1.2 Hz,
1H), 7.34 (td, J¼7.2, 1.2 Hz, 1H), 3.69 (t, J¼6.4 Hz, 2H),
2.99 (t, J¼7.6 Hz, 2H), 1.82 (q, J¼8.0 Hz, 2H), 1.70 (q,
J¼6.4 Hz, 2H), 1.50 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 138.3, 136.9, 136.3, 124.7, 124.5, 122.3, 121.3,
117.4, 62.4, 31.9, 27.9, 26.5; MS (70 eV) m/z (%): 240
(27) [M+], 196 (21), 194 (60), 187 (23), 183 (38), 181
(100); HMRS (EI) calcd for C12H13ClOS 240.0376, found
240.0379.
3.2.24. 2-(3-Pyridinyl)-3-bromobenzo[b]thiophene (4fb).
Obtained as a white solid, mp 80–81 ꢀC; 1H NMR
(400 MHz, CDCl3): d 9.00 (br s, 1H), 8.66 (br s, 1H), 8.09
(d, J¼8.0 Hz, 1H), 7.89 (d, J¼6.8 Hz, 1H), 7.83 (d,
J¼8.4 Hz, 1H), 7.51 (t, J¼8.0 Hz, 1H), 7.43–7.40 (m, 2H);
13C NMR (100 MHz, CDCl3): d 149.9, 149.3, 138.8,
137.8, 136.8, 134.1, 129.7, 125.9, 125.4, 125.1, 123.8,
122.2, 106.4; Anal. Calcd for C13H8BrNS: C, 53.81; H,
2.78; S, 11.05; N, 4.83. Found: C, 53.81; H, 2.81; S,
11.00; N, 4.76.
3.2.30. 2-Hydroxybutyl-3-bromobenzo[b]thiophene
(4ib). Obtained as a yellow oil; 1H NMR (400 MHz,
CDCl3): d 7.75 (dd, J¼7.6, 0.4 Hz, 2H), 7.41 (td, J¼7.2,
1.2 Hz, 1H), 7.35 (td, J¼8.0, 1.2 Hz, 1H), 3.70 (t,
J¼6.4 Hz, 2H), 2.99 (t, J¼7.6 Hz, 2H), 1.87–1.80 (m, 2H),
1.72–1.67 (m, 2H), 1.49 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 140.2, 138.3, 137.0, 124.9, 124.8, 122.6, 122.2,
105.9, 62.5, 31.9, 29.5, 26.5; MS (70 eV) m/z (%): 283
(43) [M+], 240 (60), 238 (58), 227 (100), 225 (96), 187
(88); HMRS (EI) calcd for C12H13BrOS 283.9870, found
283.9877.
3.2.25. 2-(20-Thienyl)-3-chlorobenzo[b]thiophene (4ga).
Obtained as a yellow solid, mp 85–86 ꢀC; 1H NMR
(400 MHz, CDCl3): d 7.83 (dd, J¼8.0, 0.8 Hz, 1H), 7.75
(dd, J¼7.6, 0.8 Hz, 1H), 7.56 (dd, J¼4.8, 1.2 Hz, 1H),
7.47–7.43 (m, 2H), 7.41 (t, J¼6.8 Hz, 1H), 7.14 (t,
J¼5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 137.7,
135.8, 134.0, 130.3, 127.4, 127.2, 127.1, 125.6, 125.1,
122.0, 121.9, 116.3; Anal. Calcd for C12H7ClS2: C, 57.48;
H, 2.81; S, 25.57. Found: C, 57.65; H, 2.84; S, 24.50.
3.2.31. 2-(2-Methyl-propanyl)-3-chlorobenzo[b]thio-
phene (4ja). Obtained as a yellow oil; 1H NMR
(400 MHz, CDCl3): d 7.76–7.73 (m, 2H), 7.43 (t,
J¼8.0 Hz, 1H), 7.36 (t, J¼8.0 Hz, 1H), 2.84 (d, J¼7.6 Hz,
2H), 2.17–2.02 (m, 1H), 1.02 (d, J¼6.8 Hz, 3H), 1.00 (d,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 137.9,
136.8, 136.5, 124.6, 124.6, 122.2, 121.3, 37.2, 30.1, 29.6,
22.3, 22.3; MS (70 eV) m/z (%): 224 (27) [M+], 187 (37),
180 (100), 147 (10), 111 (12), 109 (12); HMRS (EI) calcd
for C12H13ClS 224.0426, found 224.0425.
3.2.26. 2-(20-Thienyl)-3-bromobenzo[b]thiophene (4gb).
Obtained as a brown solid, mp 45–46 ꢀC; 1H NMR
(400 MHz, CDCl3): d 7.83 (dd, J¼8.4, 0.8 Hz, 1H), 7.76
(dd, J¼8.4, 0.8 Hz, 1H), 7.60 (dd, J¼4.0, 1.6 Hz, 1H),
7.47–7.40 (m, 2H), 7.38 (t, J¼6.8 Hz, 1H), 7.15 (t,
J¼5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 139.2,
136.6, 134.6, 132.1, 127.9, 127.2, 127.1, 125.6, 125.3,
123.4, 121.9, 104.8; Anal. Calcd for C12H7BrS2: C, 48.82;
H, 2.39; S, 21.72. Found: C, 48.57; H, 2.39; S, 21.44.
3.2.32. 2-(2-Methyl-propanyl)-3-bromobenzo[b]thio-
phene (4jb). Obtained as a yellow oil; 1H NMR
(400 MHz, CDCl3): d 7.58 (d, J¼8.0 Hz, 2H), 7.43 (t,
J¼7.2 Hz, 1H), 7.35 (t, J¼8.0 Hz, 1H), 2.85 (d, J¼7.2 Hz,
2H), 2.11–2.05 (m, 1H), 1.02 (d, J¼6.8 Hz, 3H), 1.00 (d,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 139.8,
138.2, 137.2, 124.7, 124.7, 122.7, 122.1, 106.5, 38.8, 30.1,
22.3, 22.3; MS (70 eV) m/z (%): 267 (30) [M+], 226 (100),
224 (99), 170 (10), 146 (48), 144 (49); HMRS (EI) calcd
for C12H13BrS 267.9921, found 267.9915.
3.2.27. 2-Hexyl-3-chlorobenzo[b]thiophene (4ha). Ob-
tained as a yellow oil; 1H NMR (400 MHz, CDCl3): d 7.75
(dd, J¼6.8, 1.2 Hz, 2H), 7.41 (td, J¼6.8, 0.4 Hz, 1H), 7.33
(td, J¼8.0, 1.2 Hz, 1H), 2.94 (t, J¼7.6 Hz, 2H), 1.72 (q,

W.-D. Lu, M.-J. Wu / Tetrahedron 63 (2007) 356–362
361
3.2.33. 2-tert-Butyl-3-chlorobenzo[b]thiophene (4ka).
Obtained as a yellow oil; H NMR (400 MHz, CDCl3):
107.6. These spectral data are identical to those reported in
the literature.11
1
d 7.76 (d, J¼8.0 Hz, 1H), 7.72 (d, J¼8.0 Hz, 1H), 7.41 (td,
J¼7.2, 1.2 Hz, 1H), 7.34 (td, J¼8.0, 1.2 Hz, 1H), 1.56 (s,
9H); 13C NMR (100 MHz, CDCl3): d 147.2, 138.5, 134.8,
124.6, 124.5, 121.9, 121.1, 115.2, 94.4, 35.0, 29.7, 29.5;
MS (70 eV) m/z (%): 224 (4) [M+], 209 (12), 181 (2), 159
(2), 149 (3), 58 (100); HMRS (EI) calcd for C12H13ClS
224.0426, found 224.0425.
3.2.40. 2-(4-Methylphenyl)-3-phenylbenzo[b]thiophene
(8).13 Obtained as a white solid, mp 162–163 ꢀC; 1H NMR
(400 MHz, CDCl3): d 7.88 (dd, J¼6.8, 2.0 Hz, 1H), 7.59
(dd, J¼6.8, 1.6 Hz, 1H), 7.43–7.31 (m, 7H), 7.23 (d,
J¼8.4 Hz, 2H), 7.07 (d, J¼7.6 Hz, 2H), 2.32 (s, 3H); 13C
NMR (100 MHz, CDCl3): d 140.9, 139.7, 138.7, 137.6,
135.6, 132.7, 131.2, 130.4, 129.4 (2C), 129.0 (2C), 128.6
(2C), 127.3, 124.3 (3C), 123.2, 122.0, 21.1; Anal. Calcd
for C21H16S: C, 83.96; H, 5.37; S, 10.67. Found: C, 83.96;
H, 5.28; S, 10.87.
3.2.34. 2-tert-Butyl-3-bromobenzo[b]thiophene (4kb).
Obtained as a yellow oil; H NMR (400 MHz, CDCl3):
1
d 7.80 (d, J¼8.0 Hz, 1H), 7.74 (d, J¼8.4 Hz, 1H), 7.43 (t,
J¼7.2 Hz, 1H), 7.35 (td, J¼8.0 Hz, 1H), 1.59 (s, 9H);
13C NMR (100 MHz, CDCl3): d 148.7, 139.9, 135.4,
124.7, 124.6, 122.4, 121.7, 102.6, 35.4, 30.5, 29.9, 29.9;
MS (70 eV) m/z (%): 267 (40) [M+], 256 (12), 255 (100),
253 (93), 225 (23), 174 (66); HMRS (EI) calcd for
C12H13BrS 267.9921, found 267.9919.
Acknowledgements
We thank the National Science Council of the Republic of
China for the financial support of this program.
3.2.35. 2-(Trimethylsilyl)-3-chlorobenzo[b]thiophene
(4la). Obtained as a yellow oil; 1H NMR (400 MHz,
CDCl3): d 7.85 (t, J¼7.2 Hz, 1H), 7.83 (t, J¼6.8 Hz, 1H),
7.43 (dt, J¼7.6, 1.2 Hz, 1H), 7.40 (dt, J¼7.6, 1.6 Hz, 1H),
0.45 (s, 9H); 13C NMR (100 MHz, CDCl3): d 141.2, 138.2,
133.7, 127.2, 125.0, 124.6, 122.3, 121.7, ꢁ0.90 (3C); MS
(70 eV) m/z (%): 240 (12) [M+], 224 (15), 163 (15), 149
(23), 135 (37); HMRS (EI) calcd for C11H13ClSSi
240.0196, found 240.0194.
References and notes
1. (a) Pinney, K. G.; Bounds, A. D.; Dingeman, K. M.; Mocharla,
V. P.; Pettit, G. R.; Bai, R.; Hamel, E. Bioorg. Med. Chem. Lett.
1999, 9, 1081; (b) Pinny, K. G.; Pettit, G. R.; Mocharla, V. P.;
Del, P. M.; Shirali, A. PCT Int. Appl. WO 98 39 323; Chem.
Abstr. 1998, 129, 245037c.
ꢀ
ꢀ
2. (a) Martinez, J.; Perez, S.; Oficialdegui, A. M.; Hera, B.; Orus,
L.; Villanueva, H.; Palop, J. A.; Roca, J.; Mourelle, M.; Bosch,
A.; Del Castillo, J.-C.; Lasheras, B.; Tordera, R.; del Rio, J.;
Monge, A. Eur. J. Med. Chem. 2001, 36, 55; (b) Hrib, N. J.;
Jurcak, J. G.; Bergna, D. E.; Dunn, R. W.; Geyer, H. M.;
Hartman, H. B.; Roehr, J. R.; Rogers, K. L.; Rush, D. K.;
Szczepanik, A. M.; Szewczak, M. R.; Wilmot, C. A.;
Conway, P. G. J. Med. Chem. 1992, 35, 2712.
3.2.36. 2-(Trimethylsilyl)-3-bromobenzo[b]thiophene
(4lb). Obtained as a yellow oil; 1H NMR (400 MHz,
CDCl3): d 7.84 (dd, J¼8.0, 1.2 Hz, 2H), 7.44 (t, J¼8.0 Hz,
1H), 7.37 (t, J¼8.4 Hz, 1H), 0.47 (s, 9H); 13C NMR
(100 MHz, CDCl3): d 141.3, 139.8, 125.1, 125.0, 124.7,
122.9, 122.1, 114.6, ꢁ0.80 (3C); MS (70 eV) m/z (%): 283
(41) [M+], 268 (21), 188 (26), 144 (100), 131 (39), 115
(66); HMRS (EI) calcd for C11H13BrSSi 283.9691, found
283.9699.
3. Boschelli, D. H.; Kramer, J. B.; Khatana, S. S.; Sorenson,
R. J.; Connor, D. T.; Ferin, M. A.; Wright, C. D.; Lesch,
M. E.; Imre, K.; Okonkwo, G. C.; Schrier, D. J.; Conroy,
M. C.; Ferguson, E.; Woelle, J.; Saxena, U. J. Med. Chem.
1992, 35, 958.
3.2.37. 2-[1,2-Dibromo-(2-trimethylsilylethenyl)]thioani-
sole (5lb). Obtained as a white solid, mp 97–98 ꢀC;
1H NMR (400 MHz, CDCl3): d 7.33 (t, J¼8.0 Hz, 1H),
7.17–7.11 (m, 3H), 2.47 (s, 3H), ꢁ0.05 (s, 9H); 13C NMR
(100 MHz, CDCl3): d 138.6, 134.2, 130.3, 129.7, 129.5,
124.4, 124.2, 106.9, 15.1, ꢁ0.5 (3C); Anal. Calcd for
C12H16Br2SSi: C, 37.91; H, 4.24; S, 8.43. Found: C,
37.98; H, 4.20; S, 8.54.
4. Boulware, S. L.; Bronstein, J. C.; Nordby, E. C.; Weber, P. C.
Antiviral Res. 2001, 51, 111.
5. (a) Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.;
Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemens, J. A.
J. Med. Chem. 1984, 27, 1057; (b) Palkowitz, A. D.;
Glasebrook, A. L.; Thrascher, K. J.; Hauser, K. L.; Short,
L. L.; Phillip, D. L.; Muehl, B. S.; Sato, M.; Shetler, P. K.;
Cullinan, G. J.; Pell, T. R.; Bryant, H. U. J. Med. Chem.
1997, 40, 1407.
6. Chen, Z.; Mocharla, V. P.; Farmer, J. M.; Pettit, G. R.; Hamel,
E.; Pinney, K. G. J. Org. Chem. 2000, 65, 8811.
7. Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001,
3, 651.
8. (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011;
(b) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905; (c)
Larock, R. C.; Zeni, G. Chem. Rev. 2004, 104, 2285.
9. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
10. (a) Reinecke, M. G.; Mohr, W. B.; Adickes, H. W. J. Org.
Chem. 1975, 38, 1365; (b) Ferreira, I. C. F. R.; Queiroz,
M. J. R. P.; Kirsch, G. Tetrahedron 2003, 59, 3737.
3.2.38. 2-[1,2-Dibromo-(3,3-dimethylbutenyl)]thioani-
sole (5kb). Obtained as a white solid, mp 74–75 ꢀC;
1H NMR (400 MHz, CDCl3): d 7.29–7.27 (m, 1H), 7.25–
7.07 (m, 3H), 2.49 (s, 3H), 1.11 (s, 9H); 13C NMR
(100 MHz, CDCl3): d 143.1, 139.6, 138.0, 129.2, 129.1,
124.2, 124.0, 120.6, 43.2, 31.1 (3C), 14.9; Anal. Calcd for
C13H16Br2S: C, 42.88; H, 4.43; S, 8.81. Found: C, 44.72;
H, 4.63; S, 9.00.
3.2.39. 3-Bromobenzo[b]thiophene (6lb). Obtained as
a yellow oil; 1H NMR (400 MHz, CDCl3): d 7.86–7.83 (m,
2H), 7.49 (ddd, J¼7.2, 6.0, 1.2 Hz, 1H), 7.45 (s, 1H), 7.41
(ddd, J¼8.0, 6.8, 1.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 138.5, 137.4, 125.2, 124.9, 123.4, 122.9, 122.6,

362
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11. (a) Fournier, D. C. J.; Joucla, L.; David, E.; Lemaire, M.
Tetrahedron 2004, 60, 3221; (b) Braddock, D. C.; Cansell,
G.; Hermitage, S. A. Synlett 2004, 461; (c) Patrick, G.; Jean,
L. O.; Sak, N. U.; Muhammed, E. A. E. F.; John, W. E.;
Helmut, B.; John, K. S. J. Org. Chem. 1979, 44, 2887.
Director, Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge, CB2 1EZ, UK. The deposition number is
624750.
13. Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem.
1965, 30, 587.
12. X-ray crystallographic data of compound 5lb have been
deposited with the Cambridge Crystallographic Data Center.
The coordinates can be obtained, on request, from the
14. (a) Kitamura, T.; Zhang, B. X.; Fujiwara, Y. Tetrahedron Lett.
2002, 43, 2239; (b) Patel, M. V.; Rohde, J. J.; Gracias, V.;
Kolasa, T. Tetrahedron Lett. 2003, 44, 6665.