Sanz et al.
JOCNote
SCHEME 6. Further Transformations of 3-Halobenzo-
[b]thiophenes 5 and 6
2H), 2.35 (d, J = 0.6 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.19 (t, J =
7.1 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 154.2 (C), 153.8 (C),
131.3 (C), 130.4 (CH), 130.2 (CH), 122.6 (CH), 42.4 (CH2), 42.2
(CH2), 18.4 (CH3), 14.2 (CH3), 13.3 (CH3); EI-LRMS m/z 319
(Mþ þ 2, 10), 317 (Mþ, 9), 270 (4), 138 (6), 100 (100), 72 (38);
HRMS calcd for C12H16BrNO2S 317.0085, found 317.0085.
Typical Procedure for the Synthesis of O-3-Alkynyl-
2-(methylthio)phenyl N,N-Diethylcarbamates 4. Synthesis of
O-3-(4-Methoxyphenyl)ethynyl-2-(methylthio)phenyl N,N-Diethyl-
carbamate (4b; Table 2, Entry 2). A mixture of 3ca (318 mg, 1
mmol), PdCl2(MeCN)2 (5.2 mg, 0.02 mmol), XPhos (14.3 mg, 0.03
mmol), and Cs2CO3 (977 mg, 3 mmol) in anhydrous MeCN
(2 mL) was stirred under N2 at rt for 25 min. Then, 4-methox-
yphenylacetylene (194 μL, 1.5 mmol) was added, and the reaction
was stirred at 85 °C for 3 h (the complete consumption of starting
material was monitored by GC-MS). After cooling of the reaction
mixture, EtOAc and water were added. The separated aqueous
phase was extracted with EtOAc (3 ꢀ 15 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The remaining residue was purified
by column chromatography on silica gel (eluent: hexane/EtOAc,
9/1) to afford 4b (265 mg, 72%) as a brown oil: Rf 0.34 (hexane/
EtOAc, 4/1); 1H NMR (300 MHz, CDCl3) δ 7.55-7.48 (m, 2H),
7.42 (dd, J = 7.7, 1.4 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.10 (dd,
J = 7.7, 1.4 Hz, 1H), 6.93-6.86 (m, 2H), 3.82 (s, 3H), 3.60-3.50
(m, 2H), 3.49-3.40 (m, 2H), 2.50 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H),
1.22 (t, J = 7.0 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 159.8
(C), 153.9 (C), 153.0 (C), 133.1 (2 ꢀ CH), 132.0 (C), 130.02 (CH),
129.97 (C), 128.6 (CH), 122.9 (CH), 115.2 (C), 114.0 (2 ꢀ CH),
94.5 (C), 86.7 (C), 55.3 (CH3), 42.3 (CH2), 42.1 (CH2), 18.3 (CH3),
14.2 (CH3), 13.4 (CH3); EI-LRMS m/z 369 (Mþ, 27), 322 (5),
207 (12), 100 (100), 72 (31); HRMS calcd for C21H23NO3S
369.1399, found 369.1400.
Typical Procedure for the Synthesis of O-3-Halo-2-substituted
Benzo[b]thiophene-7-yl N,N-Diethylcarbamates 5 and 6. O-3-
Iodo-2-phenylbenzo[b]thiophene-7-yl N,N-diethylcarbamate (5a;
Table 3, Entry 1). Iodine (190 mg, 0.75 mmol) was added to a
solution of 4a (169 mg, 0.5 mmol) in anhydrous CH2Cl2
(2.5 mL) at rt. The resulting mixture was stirred for 4 h
(complete cyclization was monitored by GC-MS). Saturated
aqueous Na2S2O3 solution (10 mL) was added, and the sepa-
rated aqueous phase was extracted with CH2Cl2 (2 ꢀ 10 mL).
The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The remain-
ing residue was purified by column chromatography on silica gel
(eluent: hexane/EtOAc, 9/1) to afford 5a (202 mg, 90%) as a
white solid: Rf 0.27 (hexane/EtOAc, 9/1); mp 74-76 °C; 1H
NMR (300 MHz, CDCl3) δ 7.75-7.66 (m, 3H), 7.58-7.43 (m,
4H), 7.34 (dd, J = 7.8, 0.9 Hz, 1H), 3.58-3.49 (m, 2H), 3.48-
3.38 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H);
13C NMR (75.4 MHz, CDCl3) δ 153.1 (C), 145.6 (C), 143.9 (C),
142.5 (C), 134.5 (C), 131.8 (C), 130.1 (2 ꢀ CH), 129.1 (CH),
128.6 (2 ꢀ CH), 126.2 (CH), 123.2 (CH), 118.0 (CH), 79.4 (C),
42.7 (CH2), 42.3 (CH2), 14.4 (CH3), 13.5 (CH3); EI-LRMS
m/z 451 (Mþ, 26), 323 (6), 195 (10), 152 (14), 100 (100), 72
(30); HRMS calcd for C19H18INO2S 451.0103, found 451.0106.
arylated benzo[b]thiophene derivatives,19 we synthesized 2,3-
diarylbenzothiophenes 14 and 15, which could be obtained in
high yields from 3-bromobenzothiophene 6a by Suzuki20 and
Stille21 couplings, respectively. A Sonogashira cross-coupling
allowed the preparation of 3-alkynylbenzothiophenes 16a,b
from iodo derivative 5e. Finally, 3-cyanobenzothiophene 17
could be obtained under ligand-free Pd-catalysis by treatment
of 5a with potassium ferricyanide.22
In summary, we have developed an efficient route to
regioselectively functionalized benzo[b]thiophenes using
the o-metalation and halocyclization methodologies as the
key steps. The hydroxy-substituted benzothiophene moiety
is an important scaffold in biologically active compounds.
Experimental Section
Typical Procedure for the Synthesis of O-2-Alkyl(aryl)thio-3-halo-
phenyl N,N-Diethylcarbamates 3. Synthesis of O-3-Bromo-2-(meth-
ylthio)phenyl N,N-Diethylcarbamate (3ca; Table 1, Entry 3). n-BuLi
(8.25 mL of a 1.6 M solution in hexane, 13.2 mmol) was added to a
solution of i-Pr2NH (1.85 mL, 13.2 mmol) in THF (48 mL) at 0 °C.
After 30 min at 0 °C, the LDA solution was cooled to -78 °C, and
carbamate 1c (3.25 g, 12 mmol) was added. The resulting solution
was stirred for 30 min at -78 °C, and then dimethyl disulfide
(1.27 mL, 14.4 mmol) was added. After 30 min at low temperature,
the reaction mixture was allowed to reach rt and quenched with H2O.
The aqueous phase was extracted with Et2O (3 ꢀ 30 mL), dried over
anhydrous Na2SO4, and evaporated under reduced pressure. The
resulting material was purified by column chromatography (eluent:
hexane/EtOAc, 10/1) on silica gel to afford 3ca (3.09 g, 81%) as a
white solid: Rf 0.42 (hexane/EtOAc, 4/1); mp 46-48 °C; 1H NMR
(300 MHz, CDCl3) δ 7.51-7.47 (m, 1H), 7.16 (t, J = 7.9 Hz, 1H),
7.12-7.07 (m, 1H), 3.48 (q, J = 7.1 Hz, 2H), 3.37 (q, J = 7.1 Hz,
ꢀ
Acknowledgment. We thank the Ministerio de Educacion
y Ciencia (MEC) and FEDER (CTQ2007-61436/BQU) and
ꢀ
Junta de Castilla y Leon (BU021A09 and GR-172) for
financial support. V.G. thanks MEC for a MEC-FPU pre-
doctoral fellowship.
(19) For a recent synthesis of 2,3-diarylbenzo[b]thiophenes, see: Miyasaka,
M.; Hirano, K.; Satoh, T.; Miura, M. Adv. Synth. Catal. 2009, 351, 2683–2688.
and references cited therein.
(20) Witulski, B.; Azcon, J. R.; Alayrac, C.; Arnautu, A.; Collot, V.;
Rault, S. Synthesis 2005, 771–780.
Supporting Information Available: Typical experimental
procedures and spectroscopic data for all compounds and a
copy of 1H and 13C NMR spectra. This material is available free
(21) Naber, J. R.; Buchwald, S. L. Adv. Synth. Catal. 2008, 350, 957–961.
(22) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508–1510.
7446 J. Org. Chem. Vol. 75, No. 21, 2010