(t, J ) 7.1 Hz, 3H), 1.22 (t, J ) 7.1 Hz, 3H);13C NMR (100.6
MHz, CDCl3) δ 152.9, 148.9, 130.5, 128.6, 127.8, 123.4, 123.2,
42.6, 42.2, 14.3, 13.4; EI-LRMS m/z 270 (M+-Cl, 4), 100 (100);
IR (KBr) 1716, 1415, 1243, 1156, 960 cm-1. Anal. Calcd for
for 6a in Scheme 3, it would be desirable that different
alkynes could be coupled at the C4-position of the
benzofuran. So, coupling of 5e with 1-hexyne in the
presence of PdCl2(PPh3)2 and CuI as catalysts22 afforded
4-alkynylbenzo[b]furan 6h in good yield (Scheme 4).
In summary, we have presented a practical and ef-
ficient route to 4-halo and 4-functionalized benzo[b]furans
from readily available starting materials, 3-halophenols,
and reagents, based on a tandem Sonogashira coupling/
5-endo-dig cyclization of 3-halo-2-iodophenols with alkynes.
Moreover, we have also developed an easy preparation
of 2,3-dihalophenols and current work in our laboratory
is focused on extending the synthetic scope of these
compounds.
C
11H13BrClNO2: C, 43.09; H, 4.27; N, 4.57. Found: C, 43.21; H,
4.24; N, 4.45.
General Procedure for the Deprotection of O-2,3-Di-
halophenyl N,N-Diethylcarbamates 3. Synthesis of 3-Chlo-
ro-2-iodophenol (4d; Table 2, Entry 4). To a solution of the
carbamate 3d (1.76 g, 5 mmol) in EtOH (50 mL) was added a
large excess of NaOH (2 g, 0.05 mol). The mixture was refluxed
for 8 h (completion of the hydrolysis was monitored by GC-
MS). After the mixture was cooled to room temperature, most
of the EtOH was evaporated under reduced pressure, the residue
was diluted with Et2O, and the excess of NaOH was neutralized
at 0 °C using a solution of 1 M HCl. The aqueous solution was
extracted with Et2O (3 × 20 mL), and the combined organic
layers were washed with brine, dried (Na2SO4), and evaporated
under reduced pressure. The crude was purified by column
chromatography (eluent: hexane/EtOAc, 5/1) on silica gel to
afford 4d (1.12 g, 88%): brownish solid; mp 54-56 °C (lit.11 mp
56 °C); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J ) 8.2 Hz, 1H),
7.03 (dd, J ) 8.2, 1.5 Hz, 1H), 6.88 (dd, J ) 8.2, 1.5 Hz, 1H),
5.55 (br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 156.6, 136.6,
130.3, 121.6, 111.9, 91.3; EI-LRMS m/z 256 (M+ + 2, 31), 254
(M+, 100); IR (KBr) 3275, 1568, 1435, 1272, 896, 767 cm-1. Anal.
Calcd for C6H4ClIO: C, 28.32; H, 1.58. Found: C, 28.30; H, 1.55.
General Procedure for the Synthesis of 4-Halobenzo-
[b]furans 5. Synthesis of 4-Bromo-2-phenylbenzo[b]furan
(5e; Table 3, Entry 5). To a stirred solution of phenol 4f (0.299
g, 1 mmol) and piperidine (0.085 g, 1 mmol) in DMF (1 mL)
under N2 atmosphere were added phenylacetylene (0.123 g, 1.2
mmol), Pd(OAc)2(PPh3)2 (0.015 g, 0.02 mmol), and CuI (0.008 g,
0.04 mmol). The mixture was heated at 60 °C for 5 h, and then
it was cooled to room temperature and diluted with H2O (15 mL).
The aqueous solution was extracted with Et2O (3 × 20 mL), and
the combined organic layers were dried (Na2SO4) and evaporated
under reduced pressure. The crude was purified by column
chromatography (eluent: hexane) on silica gel to afford 5e (0.197
g, 72%): white solid; mp 66-68 °C; 1H NMR (400 MHz, CDCl3)
δ 7.91-7.87 (m, 2H), 7.58-7.45 (m, 3H), 7.44-7.38 (m, 2H), 7.16
(t, J ) 8.1 Hz, 1H), 7.07 (s, 1H); 13C NMR (100.6 MHz, CDCl3)
δ 156.5, 154.5, 130.8, 129.9, 129.1, 128.9, 126.0, 125.1, 113.9,
110.3, 102.3, 101.4; EI-LRMS m/z 274 (M+ + 2, 96), 272 (M+,
Experimental Section
General Procedure for the Synthesis of O-3-Chloro- and
O-3-Fluoro-2-halophenyl N,N-Diethylcarbamates 3a-e.
Synthesis of 3-Chloro-2-iodophenyl N,N-Diethylcarbam-
ate (3d; Table 1, Entry 4). To a well-stirred solution of s-BuLi
(9.23 mL of a 1.3 M solution in cyclohexane/hexane, 12 mmol)
and TMEDA (1.81 mL, 12 mmol) in dry THF (40 mL) kept at
-78 °C under N2 atmosphere was added carbamate 1b (2.28 g,
10 mmol), and the mixture was stirred at -78 °C for 2 h. Then,
iodine (3.05 g, 12 mmol) was added and stirring continued at
low temperature for further 30 min. The reaction mixture was
then allowed to warm to room temperature, quenched with
aqueous Na2S2O3, and extracted with EtOAc (3 × 25 mL). The
combined organic layers were dried (Na2SO4) and evaporated
under reduced pressure. The crude was purified by column
chromatography (eluent: hexane/EtOAc, 10/1) on silica gel to
afford 3d (3.04 g, 86%): white solid; mp 69-71 °C; 1H NMR (400
MHz, CDCl3) δ 7.33-7.25 (m, 2H), 7.06 (dd, J ) 7.3, 2.2 Hz,
1H), 3.54 (q, J ) 7.2 Hz, 2H), 3.41 (q, J ) 7.2 Hz, 2H), 1.33 (t,
J ) 7.2 Hz, 3H), 1.23 (t, J ) 7.2 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 153.4, 152.7, 139.5, 129.5, 126.1, 121.3, 96.8, 42.4, 42.1,
14.4, 13.3; EI-LRMS m/z 353 (M+, 0.1), 100 (100); IR (KBr)
1707, 1415, 1237, 1153, 1041, 964 cm-1. Anal. Calcd for
C
11H13ClINO2: C, 37.37; H, 3.71; N, 3.96. Found: C, 37.49; H,
3.85; N, 3.89.
General Procedure for the Synthesis of O-3-Bromo- and
O-3-Iodo-2-halophenyl N,N-Diethylcarbamates 3f-k. Syn-
thesis of 3-Bromo-2-chlorophenyl N,N-Diethylcarbamate
(3h; Table 1, Entry 8). n-BuLi (4.4 mL of a 2.5 M solution in
hexane, 11 mmol) was added to a solution of i-Pr2NH (1.54 mL,
11 mmol) in THF (30 mL) at 0 °C. After 30 min at 0 °C, the
LDA solution was cooled at -78 °C and carbamate 1c (2.72 g,
10 mmol) was added. The resulting solution was stirred for 30
min at -78 °C, and then hexachloroethane (2.84 g, 12 mmol)
was added. After 30 min at low temperature, the reaction
mixture was allowed to warm to room temperature and quenched
with H2O, and THF was evaporated under reduced pressure.
The aqueous phase was extracted with EtOAc (3 × 25 mL), and
the combined organic layers were washed with HCl 1 M, dried
over anhyd Na2SO4, and evaporated under reduced pressure.
The crude was purified by column chromatography (eluent:
hexane/EtOAc, 5/1) on silica gel to afford 3h (2.82 g, 92%): white
solid; mp 40-42 °C; 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J )
8, 1.7 Hz, 1H), 7.20 (dd, J ) 8.0, 1.7 Hz, 1H), 7.14 (t, J ) 8.0
Hz, 1H), 3.49 (q, J ) 7.1 Hz, 2H), 3.40 (q, J ) 7.1 Hz, 2H), 1.30
100); IR (KBr) 1423, 1268, 1248, 1160, 1022, 908, 751, 685 cm-1
;
HRMS calcd for C14H9BrO 271.9837, found 271.9878. Anal. Calcd
for C14H9BrO: C, 61.57; H, 3.32. Found: C, 61.49; H, 3.28.
Acknowledgment. We thank the Ministerio de
Educacio´n y Ciencia and FEDER (BQU2001-1079 and
CTQ2004-08077-C02-02/BQU) and Junta de Castilla y
Leo´n (BU-24/02) for financial support. M.P.C. thanks
Junta de Castilla y Leo´n for a fellowship. Many thanks
are due to Dr. F. Rodr´ıguez (Universidad de Oviedo) for
helpful comments.
Supporting Information Available: Typical experimen-
tal procedures and spectroscopic details for all compounds not
listed in the text and a copy of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
JO0508402
J. Org. Chem, Vol. 70, No. 16, 2005 6551