Page 7 of 9
The Journal of Organic Chemistry
1H), 7.11 (dd, J = 5.0, 1.3 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H),
was further purified by silica gel column chromatography
3.89 (s, 3H), 3.19 (t, J = 6.6 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 166.3, 155.2, 138.1, 133.3, 130.5, 128.7, 125.5, 122.9,
122.1, 117.9, 113.4, 69.4, 52.3, 30.1; HRMS (ESI-TOF) m/z:
[M+NH4]+ calcd for C14H17BrNO3S 358.0107; Found,
358.0107.
to afford compound 4g as an oil (75 mg, 83% recovery);
1
2
3
4
1
FTIR (neat, cm−1) 2924, 2872, 1595, 1569, 1459, 1380; H
NMR (400 MHz, CDCl3) δ 7.24–7.17 (m, 1H), 7.17–7.00 (m,
3H), 6.85–6.71 (m, 1H), 6.63 (d, J = 8.2 Hz, 1H), 4.12 (t, J =
13
6.6 Hz, 2H), 3.12 (t, J = 6.7 Hz, 2H), 2.38 (s, 3H); C{1H}
5
6
7
8
9
NMR (101 MHz, CDCl3) δ 155.4, 139.8, 138.6, 128.9, 128.2,
127.5, 125.4, 123.1, 122.0, 110.4, 69.4, 30.3, 23.5; HRMS (ESI-
TOF) m/z: [M+NH4]+ calcd for C13H17BrNOS 314.0209;
Found, 314.0211.
3-(2-(2-Bromo-5-fluorophenoxy)ethyl)thiophene
(4c).
Compound 4c was obtained as a cloudy oil (594 mg, 99%,
1
ca. 93% purity based on H NMR analysis) and was used
directly in the next step. A retain sample (118 mg) was
further purified by silica gel column chromatography to
afford compound 4c as an oil (101 mg, 86% recovery);
FTIR (neat, cm−1) 3103, 2931, 2877, 1604, 1580, 1482, 1421; 1H
NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 8.6, 6.1 Hz, 2H),
7.24 (dd, J = 5.0, 3.0 Hz, 1H), 7.16–7.03 (m, 1H), 6.64–6.43
(m, 2H), 4.10 (t, J = 6.6 Hz, 2H), 3.13 (t, J = 6.6 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 162.7 (d, J = 247.5 Hz),
156.1 (d, J = 10.1 Hz), 138.0, 133.5 (d, J = 8.1 Hz), 128.7, 125.5,
122.1, 108.4 (d, J = 22.2 Hz), 106.3 (d, J = 4.0 Hz), 101.3 (d, J
= 27.3 Hz), 69.4, 30.0; 19F NMR (376 MHz, CDCl3) δ –111.6;
HRMS (ESI-TOF) m/z: [M]+ calcd for C12H10BrFOS
299.9614; Found, 299.9606.
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General
procedure
for
the
synthesis
of
dihydrobenzothienooxepines 2b–g via palladium-
catalyzed direct C–H arylation
Aryl ethers 4b–g (1.0 mmol), CsOAc (288 mg, 1.5 equiv),
Pd(OAc)2 (2.3 mg, 1 mol %), and dppf (11.1 mg, 2 mol %)
were charged in a septum-top vial equipped with a stir
bar. The vial was purged with nitrogen, and DMF (5 mL)
was added via syringe. The reaction was stirred at 110 °C
for 2 h and monitored by HPLC. The reaction was cooled
to 20 C and diluted with H2O (10 mL) and DCM (10 mL).
The organic layer was separated and the aqueous layer
extracted with DCM (5 mL, ×3). The combined organic
layers were washed with saturated aq NaCl solution (5
mL), dried over Na2SO4 (0.2 g), filtered, and concentrated.
The crude product was purified by silica gel column
chromatography using 0–10% i-PrOAc in heptane to
afford the desired products 2b–g.
3-(2-(2-Bromophenoxy)ethyl)thiophene (4d). Compound
4d was obtained as a clear oil (495 mg, 87%); FTIR (neat,
1
cm−1) 2928, 2875, 1584, 1480, 1464, 1441; H NMR (400
MHz, CDCl3) δ 7.52 (dd, J = 7.9, 1.6 Hz, 1H), 7.22 (ddd, J =
17.2, 8.0, 2.3 Hz, 2H), 7.15 (d, J = 2.8 Hz, 1H), 7.10 (dd, J =
5.0, 1.3 Hz, 1H), 6.88–6.75 (m, 2H), 4.18 (t, J = 6.7 Hz, 2H),
Methyl
4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-
13
3.16 (t, J = 6.7 Hz, 2H); C{1H} NMR (101 MHz, CDCl3) δ
carboxylate (2b). Aryl ether 4b (341 mg, 1 mmol) was
employed. Product 2b was obtained as a white solid (256
mg, 98 %); M.p. 79–80 ⁰C; FTIR (neat, cm−1) 2934, 2834,
155.2, 138.4, 133.4, 128.8, 128.4, 125.4, 122.0, 121.9, 113.2, 112.2,
69.2, 30.2; HRMS (ESI-TOF) m/z: [M+NH4]+ calcd for
C12H15BrNOS 300.0052; Found, 300.0049.
1
1579, 1487, 1462, 1442, 1422, 1381; H NMR (400 MHz,
3-(2-(2-bromo-5-methoxyphenoxy)ethyl)thiophene
(4e).
CDCl3) δ 7.76–7.70 (m, 1H), 7.69–7.63 (m, 2H), 7.26 (d, J =
5.1 Hz, 1H), 6.91 (d, J = 5.2 Hz, 1H), 4.37–4.28 (m, 2H), 3.90
Compound 4e was obtained as a clear oil (620 mg, 99%);
FTIR (neat, cm−1) 3101, 2934, 2834, 1579, 1487, 1463, 1442; 1H
NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 1H), 7.11 (dd,
J = 4.9, 2.9 Hz, 1H), 7.04–6.94 (m, 2H), 6.30 (d, J = 2.7 Hz,
1H), 6.23 (dd, J = 8.8, 2.8 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H),
3.60 (s, 3H), 3.01 (t, J = 6.6 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 160.2, 155.9, 138.4, 133.2, 128.9, 125.5, 122.1, 106.3,
103.0, 101.0, 69.2, 55.6, 30.2; HRMS (ESI-TOF) m/z:
[M+NH4]+ calcd for C13H17BrNO2S 330.0158; found,
330.0156.
13
(s, 3H), 3.24 (p, J = 4.9 Hz, 2H); C{1H} NMR (101 MHz,
CDCl3) δ 166.4, 157.2, 138.9, 134.9, 131.1, 129.2, 129.1, 128.2,
125.1, 124.2, 122.5, 69.9, 52.1, 33.7; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C14H13O3S 261.0580; Found, 261.0572.
8-Fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine
(2c).
Aryl ether 4c (301 mg, 1 mmol) was employed. Product 2c
was obtained as a clear oil (175 mg, 70 %); FTIR (neat,
1
cm−1) 3104, 2897, 1604, 1580, 1544, 1495, 1441, 1413; H NMR
(400 MHz, CDCl3) δ 7.67–7.58 (m, 1H), 7.15 (d, J = 5.2 Hz,
1H), 6.86 (d, J = 5.2 Hz, 1H), 6.80–6.61 (m, 2H), 4.32 (t, J =
4.8 Hz, 2H), 3.20 (t, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
161.9 (d, J = 248.5 Hz), 158.6 (d, J = 9.1 Hz), 136.3, 135.0,
130.8, 129.3 (d, J = 9.8 Hz), 123.3, 121.0, 110.4 (d, J = 21.8 Hz),
108.3 (d, J = 23.1 Hz), 70.2, 33.5; 19F NMR (376 MHz, CDCl3)
δ -114.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C12H10FOS 221.0431; Found, 221.0431.
3-(2-(2-Bromo-5-chlorophenoxy)ethyl)thiophene
(4f).
Compound 4f was obtained as a cloudy oil (595 mg,
94%); FTIR (neat, cm−1) 3097, 2929, 2877, 1579, 1462, 1377;
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.2 Hz, 1H), 7.24
(dd, J = 4.9, 2.9 Hz, 1H), 7.12 (dd, J = 2.9, 1.2 Hz, 1H), 7.07
(dd, J = 4.5, 2.0 Hz, 1H), 6.83–6.73 (m, 2H), 4.11 (t, J = 6.6
13
Hz, 2H), 3.13 (t, J = 6.5 Hz, 2H); C{1H} NMR (101 MHz,
CDCl3) δ 155.8, 138.0, 133.9, 133.8, 128.8, 125.6, 122.2, 121.9,
113.6, 110.3, 69.5, 30.1; HRMS (ESI-TOF) m/z: [M]+ calcd for
C12H10BrClOS 315.9319; Found, 315.9310.
4,5-Dihydrobenzo[b]thieno[2,3-d]oxepine (2d). Aryl ether
4d (1 mmol, 283 mg), 2 mol % of Pd(OAc)2 (4.5 mg) and 4
mol % of dppf (23 mg) were employed. Product 2d was
obtained as a yellow oil (191 mg, 94 %); FTIR (neat, cm−1)
3058, 2896, 1543, 1487, 1447, 1418, 1213; 1H NMR (400 MHz,
CDCl3) δ 7.69 (dd, J = 8.1, 1.6 Hz, 1H), 7.16 (d, J = 5.2 Hz,
1H), 7.15 – 7.09 (m, 1H), 7.01 (dtd, J = 8.3, 3.7, 1.4 Hz, 2H),
3-(2-(2-Bromo-3-methylphenoxy)ethyl)thiophene
(4g).
Compound 4g was obtained as a cloudy oil (549 mg,
1
92%, ca. 90% purity based on H NMR analysis) and was
used directly in the next step. A retain sample (90 mg)
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