Synthesis of Benzoxepinols Isolated from Butcher’s Broom
1 H), 7.48–7.31 (m, 10 H), 7.06 (dd, J = 7.2, 1.9 Hz, 2 H), 6.95–
6.89 (m, 1 H), 6.81 (dd, J = 9.0, 2.5 Hz, 1 H), 6.67 (s, 1 H), 6.63
(d, J = 2.5 Hz, 1 H), 5.21 (s, 2 H), 5.12 (s, 2 H), 5.06 (s, 2 H), 3.94
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 187.6, 164.2, 162.5,
150.4, 150.0, 149.9, 136.7, 136.1, 133.6, 131.0, 130.8, 128.9, 128.8,
128.5, 128.2, 127.7, 127.3, 121.5, 120.0, 113.6, 111.8, 110.3, 105.1,
chromatography (PE/Et2O 0:1, Rf = 0.48). Compound 11c was iso-
lated in 67 % yield (63 mg, 0.21 mmol). 1H NMR (300 MHz,
MeOD): δ = 7.68 (d, J = 8.7 Hz, 1 H), 6.94 (d, J = 1.8 Hz, 1 H),
6.79 (dd, J = 8.2, 1.8 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 6.57 (dd,
J = 8.7, 2.3 Hz, 1 H), 6.49 (d, J = 2.3 Hz, 1 H), 4.37 (dd, J = 12.2,
6.4 Hz, 1 H), 4.19 (dd, J = 12.2, 7.1 Hz, 1 H), 3.84 (s, 3 H), 3.58–
3.43 (m, 1 H), 3.15–2.99 (m, 2 H) ppm. 13C NMR (75 MHz,
71.8, 71.0, 70.5, 56.3 ppm. FTIR: ν = 697, 735, 1023, 1145, 1248,
˜
1514, 1593, 1738, 2875, 2935, 3031, 3063 cm–1. ESI-MS: m/z (%) = MeOD): δ = 200.3, 167.2, 164.8, 149.2, 146.7, 135.2, 132.3, 122.0,
280.3 (10), 479.2 (100) [M + H]+. HRMS (ESI): calcd. for
C31H27O5 [M + H]+ 479.1853; found 479.1849.
120.9, 116.4, 112.2, 112.0, 107.5, 80.6, 56.4, 45.5 ppm. FTIR: ν =
˜
539, 735, 794, 819, 856, 1024, 1109, 1157, 1212, 1238, 1268, 1449,
1467, 1517, 1576, 1598, 1651, 2844, 2938, 2966, 3062, 3345 cm–1.
ESI-MS: m/z (%) = 301.1 (100) [M + H]+. HRMS (ESI): calcd. for
C17H17O5 [M + H]+ 301.1071; found 301.1069.
7-(Benzyloxy)-3-[4-(benzyloxy)-3-methoxyphenyl]-8-methoxybenzo-
[b]oxepin-5(2H)-one (2d): The crude product was purified by flash
chromatography (PE/EtOAc 2:1, Rf = 0.32). Compound 2d was
obtained as a pale white solid in 53% yield (135 mg, 0.27 mmol),
m.p. 82–85 °C. 1H NMR (300 MHz, CDCl3): δ = 7.66 (s, 1 H),
7.52–7.28 (m, 10 H), 7.10–7.03 (m, 2 H), 6.92 (d, J = 8.9 Hz, 1 H),
6.66 (s, 1 H), 6.57 (s, 1 H), 5.21 (s, 2 H), 5.16 (s, 2 H), 5.05 (s, 2
H), 3.94 (s, 3 H), 3.92 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 187.1, 156.8, 155.4, 150.2, 149.8, 149.7, 144.6, 136.7, 136.6,
130.8, 130.7, 128.7, 128.6, 128.0, 127.7, 127.2, 119.9, 119.8, 113.7,
7-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-8-methoxy-3,4-dihydro-
benzo[b]oxepin-5(2H)-one (11d): The crude product was purified by
flash chromatography (PE/EtOAc 2:1, Rf = 0.22). Compound 11d
was isolated in 65% yield (42 mg, 0.13 mmol). 1H NMR (300 MHz,
CDCl3): δ = 7.38 (s, 1 H), 6.87 (d, J = 8.1 Hz, 2 H), 6.87 (d, J =
1.8 Hz, 1 H), 6.82 (dd, J = 8.2, 1.8 Hz, 1 H), 6.62 (s, 1 H), 5.60 (s,
1 H), 5.45 (s, 1 H), 4.35 (dd, J = 12.1, 6.5 Hz, 1 H), 4.26 (dd, J =
12.1, 6.5 Hz, 1 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 3.48 (p, J = 6.5 Hz,
1 H), 3.19 (dd, J = 12.6, 8.2 Hz, 1 H), 3.09 (dd, J = 12.6, 6.4 Hz,
1 H) ppm. 13C NMR (101 MHz, MeOD): δ = 200.4, 159.8, 154.6,
149.2, 146.7, 143.6, 135.1, 122.2, 121.0, 116.4, 114.5, 112.0, 104.8,
113.5, 110.2, 103.0, 71.9, 71.1, 70.9, 56.3, 56.2 ppm. FTIR: ν = 695,
˜
736, 1006, 1140, 1206, 1505, 1596, 1738, 2341, 2359, 2871, 2939,
3033, 3063 cm–1. ESI-MS: m/z (%) = 509.2 (100) [M + H]+, 567.2
(5) [M + NH4 + MeCN]+, 1039.4 (9) [2M + Na]+. HRMS (ESI):
calcd. for C32H29O6 [M + H]+ 509.1959; found 509.1957.
80.8, 56.6, 56.4, 45.3 ppm. FTIR: ν = 827, 1031, 1151, 1208, 1270,
˜
1362, 1443, 1504, 1613, 1656, 2953, 3418 cm–1. ESI-MS: m/z (%) =
331.1 (100) [M + H]+. HRMS (ESI): calcd. for C18H19O6 [M + H]+
331.1176; found 331.1178.
Typical Procedure for Hydrogenation
8-Hydroxy-3-(4-hydroxyphenyl)-3,4-dihydrobenzo[b]oxepin-5(2H)-
one (11a): Compound 2a (0.14 g, 0.32 mmol) was dissolved in
EtOAc/MeOH (2:1, 35 mL), and Pd/C (35 mg) was added. The re-
action mixture was placed in a flask equipped with a hydrogen-
filled balloon and stirred for 6 h under a H2 atmosphere. The mix-
ture was filtered through Celite, and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography (PE/EtOAc 2:1, Rf = 0.14). Compound 11a was
isolated in 58% yield (50 mg, 0.11 mmol). 1H NMR (300 MHz,
MeOD): δ = 7.67 (d, J = 8.7 Hz, 1 H), 7.22–7.13 (m, 2 H), 6.77–
6.69 (m, 2 H), 6.56 (dd, J = 8.7, 2.3 Hz, 1 H), 6.48 (d, J = 2.3 Hz,
1 H), 4.35 (dd, J = 12.2, 6.3 Hz, 1 H), 4.19 (dd, J = 12.2, 6.9 Hz,
1 H), 3.56–3.43 (m, 1 H), 3.08 (dd, J = 12.6, 7.7 Hz, 1 H), 3.00
(dd, J = 12.6, 6.9 Hz, 1 H) ppm. 13C NMR (75 MHz, MeOD): δ
= 200.2, 167.2, 164.8, 157.6, 134.5, 132.3, 129.5, 122.0, 116.5, 112.1,
Typical Procedure for the Final Reduction Elimination Step
3-(4-Hydroxyphenyl)-2,3-dihydrobenzo[b]oxepin-8-ol (1a): Com-
pound 11a (30 mg, 0.21 mmol) was dissolved in EtOH (15 mL).
The solution was cooled to 0 °C before NaBH4 (31 mg, 0.55 mmol)
was added. The reaction mixture was stirred for 3 h at 0 °C and an
additional 20 h at room temperature. The progress of the reaction
was monitored by TLC. After the consumption of the substrate,
the reaction mixture was cool with an ice–water bath and quenched
by the addition of 1 n HCl (2 mL) and stirred overnight. The EtOH
was removed under reduced pressure, and the remaining reaction
solution was extracted with Et2O (4ϫ 10 mL). The combined or-
ganic phases were dried with MgSO4, and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (PE/EtOAc 2:1, Rf = 0.24). Compound 1a was
obtained as a white solid in 46% yield (13 mg, 0.051 mmol). 1H
NMR (600 MHz, MeOD): δ = 7.10–7.03 (m, 3 H), 6.76–6.71 (m,
2 H), 6.48 (dd, J = 8.4, 2.5 Hz, 1 H), 6.41–6.34 (m, 2 H), 5.78 (dd,
J = 11.8, 4.1 Hz, 1 H), 4.23 (ddd, J = 11.7, 3.2, 0.8 Hz, 1 H), 4.07
(dd, J = 11.6, 6.7 Hz, 1 H), 3.88–3.82 (m, 1 H) ppm. 13C NMR
(151 MHz, MeOD): δ = 161.7, 158.8, 157.4, 134.8, 133.5, 131.1,
107.5, 80.6, 45.1 ppm. FTIR: ν = 532, 737, 830, 1020, 1111, 1160,
˜
1244, 1448, 1515, 1596, 1648, 2853, 2924, 3026, 3293 cm–1. APCI-
MS: m/z (%) = 271.1 (100) [M + H]+. HRMS (ESI): calcd. for
C16H15O4 [M + H]+ 271.0965; found 271.0969.
7-Hydroxy-3-(4-hydroxyphenyl)-8-methoxy-3,4-dihydrobenzo[b]-
oxepin-5(2H)-one (11b): Compound 11b was obtained as a colour-
less oil in 85 % yield (0.11 g, 0.37 mmol). 1H NMR (600 MHz,
MeOD): δ = 7.20 (s, J = 4.6 Hz, 1 H), 7.18–7.13 (m, 2 H), 6.76–
6.72 (m, 2 H), 6.71 (s, 1 H), 4.33 (dd, J = 12.1, 6.6 Hz, 1 H), 4.17
(dd, J = 12.1, 7.2 Hz, 1 H), 3.90 (s, J = 5.2 Hz, 3 H), 3.50–3.44 (m,
1 H), 3.12 (dd, J = 12.9, 8.2 Hz, 1 H), 3.00 (dd, J = 12.9, 6.0 Hz,
1 H) ppm. 13C NMR (151 MHz, MeOD): δ = 200.4, 159.8, 157.6,
154.6, 143.6, 134.4, 129.4, 122.2, 116.5, 114.5, 104.8, 80.8, 56.6,
130.4, 128.9, 120.0, 116.2, 111.0, 107.3, 76.4, 50.7 ppm. FTIR: ν =
˜
732, 820, 1115, 1161, 1248, 1511, 1611, 2923, 2957, 3066, 3376
cm–1. ESI-MS: m/z (%) = 107.1 (49), 147.1 (100), 239.1 (24), 254.1
(41) [M]+·. HRMS: calcd. for C16H14O3 [M]+· 254.0943; found
254.0943.[2]
3-(4-Hydroxyphenyl)-8-methoxy-2,3-dihydrobenzo[b]oxepin-7-ol
(1b): The crude product was purified by flash chromatography
(DCM/CH3CN/PE 1:1:1.5, Rf = 0.44). Compound 1b was obtained
49.7, 44.9 ppm. FTIR: ν = 532, 834, 1209, 1267, 1445, 1515, 1613,
˜
1699, 2963, 3087, 3216 cm–1. ESI-MS: m/z (%) = 272.6 (35), 301.0
(100) [M + H]+, 318.0 (60) [M + NH4]+, 342.0 (50) [M + H +
MeCN]+. HRMS (ESI): calcd. for C17H17O5 [M + H]+ 301.1071;
found 301.1070.
1
in 42% yield (44 mg, 0.15 mmol). H NMR (300 MHz, MeOD): δ
= 7.07–7.01 (m, 2 H), 6.74–6.69 (m, 2 H), 6.66 (s, 1 H), 6.52 (s, 1
H), 6.28 (dd, J = 12.0, 1.9 Hz, 1 H), 5.81 (dd, J = 11.8, 4.1 Hz, 1
H), 4.19 (dd, J = 11.5, 3.1 Hz, 1 H), 4.03 (dd, J = 11.6, 6.6 Hz, 1
H), 3.87–3.82 (m, 1 H), 3.80 (s, 3 H) ppm. 13C NMR (75 MHz,
8-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-3,4-dihydrobenzo[b]-
oxepin-5(2H)-one (11c): The crude product was purified by flash
Eur. J. Org. Chem. 2014, 3170–3181
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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