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ther stirring for 1 h at ambient temperature. After complete con-
sumption of starting materials (monitored by TLC), Pd(OAc)2
(44 mg, 0.2 mmol), Cu(OAc)2 (182 mg, 1.0 mmol), and Bu4NBr
(65 mg, 0.2 mmol) were added and the reaction mixture was
heated at 908C with continuous stirring for 4–6 h (monitored by
TLC). The reaction mixture was diluted with sat. aq NH4Cl (25 mL),
extracted with EtOAc (325 mL), and the combined organic layer
was washed with water (325 mL), brine (225 mL), dried
(Na2SO4), and concentrated under reduced pressure to give the
crude products, which were purified by column chromatography
over silica gel (EtOAc/hexane).
4,7-Dimethoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-car-
bonitrile (4l): Obtained from acetonitrile 5j and dithioester 2a by
Method A as a yellow liquid (130 mg, 59%). Rf 0.6 (EtOAc/hexane,
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1:4); H NMR (400 MHz, CDCl3): d=7.51 (d, J=8.8 Hz, 2H), 7.00 (d,
J=8.8 Hz, 2H), 6.93 (d, J=2.8 Hz, 1H), 6.87 (d, J=2.8 Hz, 1H), 3.87
(s, 3H), 3.85 (s, 3H), 3.80 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=161.0, 153.6, 151.2, 131.8, 131.6, 127.8, 123.0, 116.7, 116.1,
113.9, 113.5, 112.8, 107.8, 56.4, 56.0, 55.4 ppm; IR (neat): n˜ =2937,
2204, 1602, 1494, 1225, 1020 cmÀ1; HRMS (ESI): m/z calcd for
C18H16NO3S: 326.0851 [M+H]+; found: 326.0835.
(2-Butylbenzo[b]thiophen-3-yl)(phenyl)methanone (4q): Ob-
tained from deoxybenzoin 5m and dithioester 2l as a brown liquid
(75 mg, 50% by Method A; 62 mg, 45% by Method B; 115 mg,
Two-step procedure from enethiols 6 (Method B): All the desired
enethiols 6e–f, 6i, 6o–q, 6s, 6u, 6w, 12 f, and 12i–j were pre-
pared in nearly quantitative yields from the respective arylacetoni-
triles, deoxybenzoin or aryl acetates (1.0 mmol), and the corre-
sponding dithioesters (1.0 mmol), by following a similar procedure
to that described for the preparation of enethiol 6a. These crude
enethiols were used as such for the next step without further pu-
rification. The crude enethiols 6e–f, 6i, 6o–q, 6s, 6u, 6w, 12 f, and
12i–j (1.0 mmol) were subjected to intramolecular arylthiolation in
the presence of Pd(OAc)2 (44 mg, 0.2 mmol), Cu(OAc)2 (182 mg,
1.0 mmol), and Bu4NBr (65 mg, 0.2 mmol) in DMF (6 mL) at 908C
for 8–10 h (monitored by TLC) by following a similar procedure
and work-up to that described for the synthesis of benzo[b]thio-
phene 4a. The benzo[b]- and hetero-fused thiophenes 4 f, 4o–q,
4s, 4u, 4w, 13 f, and 13i, thus obtained, were further purified by
column chromatography over silica gel (EtOAc/hexane).
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78% by Method C). Rf 0.6 (EtOAc/hexane, 2:8); H NMR (400 MHz,
[D6]DMSO): d=8.01–7.99 (m, 1H), 7.76–7.74 (m, 2H), 7.72–7.67 (m,
1H), 7.55 (t, J=8.0 Hz, 2H), 7.38–7.29 (m, 3H), 2.78 (t, J=7.6 Hz,
2H), 1.58 (quin, J=7.6 Hz, 2H), 1.22 (quin, J=7.6 Hz, 2H), 0.76 ppm
(t, J=7.2 Hz, 3H); 13C NMR (100 MHz, [D6]DMSO): d=192.9, 150.3,
138.2, 137.9, 137.2, 133.6, 131.5, 129.1, 128.9, 124.8, 124.4, 122.5,
122.3, 33,1, 28.6, 21.4, 13.3 ppm; IR (neat): n˜ =2925, 1650, 1434,
1230, 1167, 1069, 755 cmÀ1; HRMS (ESI): m/z calcd for C19H19OS:
295.1157 [M+H]+; found: 295.1156.
Methyl 2-(furan-2-yl)benzo[b]thiophene-3-carboxylate (4t): Ob-
tained from acetate 5p and dithioester 2m by Method A as
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a brown liquid (132 mg, 77%). Rf 0.6 (EtOAc/hexane, 2:8); H NMR
(400 MHz, CDCl3): d=7.51 (d, J=1.2 Hz, 1H), 7.42–7.36 (m, 4H),
6.69 (d, J=0.8 Hz, 1H), 6.50 (dd, J=3.2, 1.6 Hz, 1H), 3.68 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=168.4, 150.1, 143.8, 136.3,
135.7, 133.6, 129.6, 128.8, 128.7, 128.4, 128.3, 113.4, 111.7,
52.5 ppm; IR (neat): n=1718, 1535, 1430, 1289, 1196, 1012,
739 cmÀ1; HRMS (ESI): m/z calcd for C14H11O3S: 259.0429 [M+H]+;
found: 259.0428.
Two-step procedure with oxygen as reoxidant (Method C):
Pd(OAc)2 (44 mg, 0.2 mmol) was added to a solution of crude ene-
thiol 6o, 6q, 6u, 6w, and 12j (1.0 mmol), prepared as described
above in DMF (5 mL), and the reaction mixture was heated at 908C
under O2 atmosphere with continuous stirring for 8–12 h (moni-
tored by TLC). The reaction mixture was diluted with sat. aq NH4Cl
(25 mL), extracted with EtOAc (325 mL), and the combined or-
ganic layer was washed with water (325 mL), brine (225 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
crude products were purified by column chromatography over
silica gel (EtOAc/hexane). Spectral and analytical data of represen-
tative benzo[b]thiophenes and the corresponding hetero-fused thi-
ophenes are given below.
(4-(4-Methoxybenzyloxy)phenyl)(6-methoxy-2-(4-methoxyphe-
nyl)benzo[b]thiophen-3-yl)methanone (4u): Obtained from deox-
ybenzoin 5q and dithioester 2a as a brown liquid (63 mg, 45% by
Method A; 60 mg, 43% by Method B; 101 mg, 72% by Method C).
Rf 0.4 (EtOAc/hexane, 3:7); 1H NMR (400 MHz, CDCl3): d=7.77 (d,
J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H),
7.32–7.29 (m, 3H), 6.95 (dd, J=9.2, 2.4 Hz, 1H), 6.90 (d, J=8.8 Hz,
2H), 6.83 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.97 (s, 2H),
3.88 (s, 3H), 3.81 (s, 3H), 3.75 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=193.4, 163.1, 159.9, 159.8, 157.8, 142.6, 140.2, 134.1,
132.5, 130.8, 130.7, 130.4, 129.4, 128.2, 126.2, 124.2, 114.9, 114.6,
114.2, 104.7, 70.1, 55.8, 55.44, 55.39 ppm; IR (neat): n˜ =3057, 1652,
1560, 1404, 1064, 852 cmÀ1; HRMS (ESI): m/z calcd for C31H27O5S:
511.1579 [M+H]+; found: 511.1598.
5-Chloro-2-(5-(dimethylamino)thiophen-2-yl)benzo[b]thiophene-
3-carbonitrile (4 f): Obtained from acetonitrile 5e and dithioester
2 f as a brown solid (141 mg, 67% by Method A; 160 mg, 76% by
Method B). M.p.193–1958C; Rf 0.7 (EtOAc/hexane, 1:4); 1H NMR
(400 MHz, CDCl3): d=7.72 (d, J=2.0 Hz, 1H), 7.56 (d, J=6.0 Hz,
1H), 7.54 (d, J=1.6 Hz, 1H), 7.25 (dd, J=8.4, 2.0 Hz, 1H), 5.89 (d,
J=8.4 Hz, 1H), 3.07 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
163.2, 151.3, 140.9, 133.2, 132.6, 131.6, 130.8, 125.4, 122.9, 121.0,
116.2, 116.0, 103.0, 42.5 ppm; IR (neat): n˜ =2921, 2197, 1700, 1633,
1548, 1194, 911 cmÀ1; HRMS (ESI): m/z calcd for C15H12ClN2S2:
319.0130 and 321.0101 [M+H]+; found: 319.0120 and 320.9992.
Deprotection of 4p with TFA—synthesis of (4-hydroxyphenyl)(6-
methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone
(4v): Compound 4u 100 mg, 0.2 mmol) was dissolved in trifluoro-
acetic acid (5 mL) and heated to reflux for 5 h (monitored by TLC).
The reaction mixture was poured in ice-cold water and extracted
with CH2Cl2 (325 mL) and the combined organic layer was
washed with water (325 mL), brine (225 mL), dried (Na2SO4),
and concentrated. The crude products were purified by silica gel
column chromatography (EtOAc/hexane) to give pure 4v (57 mg,
2-(4-(Piperidin-1-yl)phenyl)benzo[b]thiophene-3,6-dicarbonitrile
(4h): Obtained from acetonitrile 5g and dithioester 2h by Meth-
od A as an orange solid (198 mg, 82%). M.p. 212–2148C; Rf 0.8
(EtOAc/hexane, 1:4); 1H NMR (400 MHz, CDCl3): d=8.08 (d, J=
0.8 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.70
(dd, J=8.4, 1.2 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 3.39–3.37 (m, 4H),
1.71–1.69 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=160.1, 153.4,
143.0, 136.3, 129.7, 128.9, 126.6, 122.6, 119.3, 118.8, 115.3, 114.7,
108.7, 98.8, 48.8, 25.5, 24.5 ppm; IR (neat): n˜ =2224, 2209, 1603,
1485, 1314, 1166, 803 cmÀ1; HRMS (ESI): m/z calcd for C21H18N3S:
344.1221 [M+H]+; found: 344.1216.
1
75%) as a yellow oil. Rf 0.2 (EtOAc/hexane, 8:2); H NMR (400 MHz,
CDCl3): d=7.71 (d, J=8.8 Hz, 2H), 5.52 (d, J=8.8 Hz, 1H), 7.34–7.31
(m, 3H), 6.95 (dd, J=9.2, 2.4 Hz, 1H), 6.75 (d, J=8.8 Hz, 2H), 6.68
(d, J=8.8 Hz, 2H), 5.78 (br s, 1H), 3.88 (s, 3H), 3.74 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=193.5, 160.4, 159.9, 157.8, 143.0,
140.2, 134.1, 132.8, 130.7, 130.5, 129.8, 126.2, 124.2, 115.4, 115.0,
114.2, 104.7, 55.8, 55.4 ppm; IR (neat): n˜ =3450–3057, 2919, 1651,
Chem. Eur. J. 2015, 21, 17116 – 17125
17123
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