Journal of Medicinal Chemistry
ARTICLE
chromatography (Hex:EtOAc, 4:1) to give (i) 24 (111.5 mg, 60% yield)
as a light yellow solid and (ii) 25 (4.8 mg, 0.0161 mmol, 2.5% yield) as a
yellow solid. 1H NMR (400 MHz) CDCl3: 11.5 (s, 1H), 7.69ꢀ7.66 (d,
2H), 7.52ꢀ7.49 (d, 1H), 6.99ꢀ6.95 (d, 2H), 6.91ꢀ6.89 (d, 1H), 5.60
(s, 1H), 3.91 (s, 3H), 2.68ꢀ2.53 (q, 2H), 1.21ꢀ1.17 (t, 3H). 13C NMR
(100 MHz) CDCl3: 199.1, 163.0, 162.3, 159.4, 148.4, 132.2, 131.4,
129.5, 118.3, 113.6, 113.2, 111.8, 102.9, 55.5, 21.8, 11.8. LC/MS-MS:
297.0 f 189.0 m/z; GS1 and GS2 at 25, CAD = 5, DP = 71, CE = 29,
CXP = 12, tR = 4.80 min. (iii) Compound 26 (8.5 mg, 0.0301 mmol, 5%
mg) was added, and the contents were warmed (105ꢀ110 °C, 1.0 h).
The mixture was quenched [2 vol of saturated NH4Cl(aq)] and
extracted with EtOAc (4 ꢁ 150 mL). The organic phase was washed
with H2O, followed by NaCl(aq) and then dried (MgSO4). The material
was filtered, concentrated under reduced pressure, and purified via SiO2
chromatography (4:1, Hex:EtOAc) to afford 30 as a yellow solid (1.54 g,
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5.20 mmol, 81% yield). H NMR (400 MHz) CDCl3: 10.3 (bs, 1H),
7.79ꢀ7.78 (d, 2H), 7.28ꢀ7.26 (d, 1H), 7.02ꢀ7.01 (d, 1H), 6.93ꢀ6.91
(d, 2H), 6.84ꢀ6.82 (dd, 1H), 3.85 (s, 3H), 2.90ꢀ2.84 (q, 2H),
1.33ꢀ1.29 (t, 3H). 13C NMR (100 MHz) CDCl3: 191.8, 165.0, 161.0,
157.9, 154.6, 132.1, 131.2, 121.4, 120.3, 116.0, 115.5, 112.2, 95.8, 55.7, 21.8,
12.4. LC/MS-MS: 297.0 f 121.2 m/z; GS1 and GS2 at 25, DP = 46, CE =
27, CXP = 6, tR = 4.28 min.
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yield) as a yellow foam. H NMR (400 MHz) CDCl3: 11.5 (bs, 1H),
7.65ꢀ7.61 (d, 2H), 7.52ꢀ7.50 (d, 1H), 6.93ꢀ6.89 (m, 3H), 5.60 (s,
1H), 5.24 (bs, 1H), 2.68ꢀ2.63 (q, 2H), 1.21ꢀ1.17 (t, 3H). 13C NMR
(100 MHz) CDCl3: 199.1, 162.4, 159.4, 159.3, 148.5, 132.4, 131.6,
129.5, 118.4, 115.2, 113.2, 111.7, 102.8, 21.8, 11.8. LC/MS-MS: 283.1 f
189.0 m/z; GS1 and GS2 at 25, CAD = 5, DP = 66, CE = 29, CXP = 12,
tR = 4.26 min.
(2-Ethyl-5-methoxybenzofuran-7-yl)(4-hydroxyphenyl)methanone
(27). In a RBF/SB (50 mL), 16 (2.17 g, 6.99 mmol) dissolved in DMF
(26 mL) was added and stirred. NaSEt (884 mg) was added and heated
(100ꢀ105 °C, 3.0 h). The reaction mixture was quenched [2 vol of
NH4Cl(aq)] and extracted with EtOAc (4 ꢁ 125 mL). The organic
phase was washed with H2O and NaCl(aq), dried (MgSO4), filtered,
concentrated under reduced pressure, and purified via SiO2 chromatog-
raphy (2:1, Hex:EtOAc) to afford 27 as a light yellow sticky solid (908
mg, 3.06 mmol, 44% yield). 1H NMR (400 MHz) CDCl3: 10.3 (bs, 1H),
7.78ꢀ7.75 (d, 2H), 7.39 (s, 1H), 7.02 (s, 1H), 6.87ꢀ6.83 (d, 2H), 6.38
(s, 1H), 3.74 (s, 3H), 2.82ꢀ2.77 (q, 2H), 1.30ꢀ1.26 (t, 3H). 13C NMR
(100 MHz) CDCl3: 192.0, 165.0, 161.4, 157.8, 154.5, 132.1, 130.9,
121.3, 120.3, 116.0, 115.5, 112.2, 95.7, 55.7, 21.8, 12.3. LC/MS-MS:
297.0 f 203.1 m/z; GS1 and GS2 at 25, DP = 36, CE = 27, CXP = 14,
tR = 4.20 min.
(2-Ethyl-5-hydroxybenzofuran-7-yl)(4-methoxyphenyl)methanone
(28). In a RBF/SB (25 mL), 16 (0.200 g, 0.644 mmol) was diluted with
DMF (4.5 mL), and NaSEt (0.108 g, 1.28 mmol) was added. The
mixture was heated (110 ( 5 °C, 1.0 h) and then quenched with
NH4Cl(aq) (2 vol), and extracted with EtOAc (3 ꢁ 75 mL). The
organic phase was dried (Na2SO4), filtered, concentrated under reduced
pressure, and purified via SiO2 chromatography (Hex:EtOAc, 4:1) to
give (i) 27 (97.0 mg, 0.327 mmol, 51% yield) as a white solid and (ii) 28
(8.1 mg, 0.027 mmol, 4% yield) as a yellow solid. 1H NMR (400 MHz)
CDCl3: 11.9 (s, 1H), 7.74ꢀ7.72 (d, 2H), 7.63 (s, 1H), 7.07 (s, 1H),
7.02ꢀ7.00 (d, 2H), 6.36 (s, 1H), 3.91 (s, 3H), 2.81ꢀ2.76 (q, 2H),
1.35ꢀ1.31 (t, 3H). 13C NMR (100 MHz) CDCl3: 199.9, 167.1, 162.6,
158.9, 147.6, 136.6, 131.6, 130.8, 115.2, 114.3, 113.6, 107.1, 101.6, 55.5,
22.1, 11.5. LC/MS-MS: 297.0 f 135.0 m/z; GS1 and GS2 at 25, DP =
106, CE = 33, CXP = 8, tR = 4.82 min.
(2-Ethyl-5-hydroxybenzofuran-7-yl)(4-hydroxyphenyl)methanone (29).
In aRBF/SB(25 mL), 16 (0.200 g, 0.644 mmol) was added and diluted with
DMF (4.5 mL). NaSEt (0.270 g, 3.22 mmol) was added, and the contents
were stirred and heated (110 ( 5 °C, 16 h). Next, the reaction mixture was
quenched with NH4Cl(aq) and extracted with EtOAc (3 ꢁ 75 mL). The
organic phase was washed with NaCl(aq), dried (Na2SO4), filtered, con-
centrated under reduced pressure, and purified via SiO2 chromatography
(Hex:EtOAc, 4:1) to give (i) 27 (82.0 mg, 0.276 mmol, 43% yield) as an off-
white solid and (ii) 29 (21.3 mg, 0.075 mmol, 12% yield) as a yellow solid. 1H
NMR (400 MHz) CDCl3: 11.9 (bs, 2H), 7.69ꢀ7.67 (d, 2H), 7.62 (s, 1H),
7.07 (s, 1H), 6.95ꢀ6.93 (d, 2H), 6.36 (s, 1H), 2.80ꢀ2.78 (q, 2H),
1.35ꢀ1.32 (t, 3H). 13C NMR (100 MHz) CDCl3: 200.0, 167.2, 159.1,
158.8, 147.6, 136.8, 131.9, 131.0, 115.2, 115.1, 114.4, 107.2, 101.7, 22.1, 11.5.
LC/MS-MS: 283.1 f 121.2 m/z; GS1 and GS2 at 25, DP = 61, CE = 33,
CXP = 6, tR = 4.37 min.
(2-Ethyl-6-hydroxybenzofuran-3-yl)(4-methoxyphenyl)methanone
(31) and (2-Ethyl-6-hydroxybenzofuran-3-yl)(4-hydroxyphenyl)met-
hanone (32). A RBF/SB containing AlCl3 (0.403 g, 3.03 mmol) was
cooled with an ice/NaCl bath (10 min), and then, HSEt (0.829 mL) was
added and mixed. Compound 17 (0.200 g, 0.644 mmol) in DCM
(4.3 mL) was added and stirred (1.0 h). Afterward, the reaction was
quenched (1.0 N HCl, 5 mL) and extracted (DCM). The organic phase
was washed with NaCl(aq), dried (Na2SO4), filtered, concentrated
under reduced pressure, and then purified via SiO2 chromatography
(Hex:EtOAc, 4:1) to give (i) 31 (107.8 mg, 0.364 mmol, 56% yield) as a
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yellow foam. H NMR (400 MHz) DMSO-d6: 7.86ꢀ7.84 (d, 2H),
7.21ꢀ7.19 (d, 1H), 7.00 (s, 1H), 6.96ꢀ6.94 (d, 2H), 6.79ꢀ6.76 (m,
2H), 3.88 (s, 3H), 2.88ꢀ2.82 (q, 2H), 1.32ꢀ1.28 (t, 3H). 13C NMR
(100 MHz) DMSO-d6: 191.5, 164.8, 163.6, 154.5, 154.1, 131.8, 131.7,
121.4, 120.2, 116.0, 113.7, 112.6, 98.1, 55.5, 21.7, 12.4. LC/MS-MS:
297.0 f 135.1 m/z; GS1 and GS2 at 25, CAD = 6, DP = 66, CE = 31,
CXP = 8, tR = 4.24 min. (ii) Compound 32 (14.7 mg, 0.052 mmol, 8%
yield) as a light yellow solid. 1H NMR (400 MHz) DMSO-d6: 10.4 (bs,
1H), 9.6 (bs, 1H), 7.67ꢀ7.65 (d, 2H), 7.14ꢀ7.12 (d, 1H), 6.94ꢀ6.93
(d, 1H), 6.88ꢀ6.86 (d, 2H), 6.73ꢀ6.71 (d, 1H), 2.75ꢀ2.69 (q, 2H),
1.21ꢀ1.18 (t, 3H). 13C NMR (100 MHz) DMSO-d6: 189.9, 162.8,
162.5, 156.0, 154.6, 132.0, 130.3, 121.3, 119.1, 116.1, 115.7, 113.1, 97.9,
21.6, 12.8. LC/MS-MS: 283.0 f 121.2 m/z; GS1 and GS2 at 25, CAD =
5, DP = 41, CE = 29, CXP = 6, tR = 4.45 min.
(2-Ethyl-6-methoxybenzofuran-4-yl)(4-hydroxyphenyl)methanone
(33). In a RBF/SB, 18 (700 mg, 2.26 mmol) was diluted with DMF
(11 mL). To the mixture NaSEt (367 mg) was added, and the contents
were warmed (105ꢀ110 °C, 3.0 h). Afterward, the reaction was
quenched [2 vol of NH4Cl(aq)] and extracted with EtOAc (4 ꢁ
70 mL). The organic phase was washed with H2O, NaCl(aq), dried
(MgSO4), filtered, concentrated under reduced pressure, and purified
via SiO2 chromatography (4:1, Hex:EtOAc) to afford 33 as a yellow
solid (308 mg, 1.04 mmol, 46% yield). 1H NMR (400 MHz) DMSO-d6:
10.4 (bs, 1H; exchangeable in D2O), 7.59ꢀ7.57 (d, 2H), 7.38 (s, 1H),
7.33 (s, 1H), 6.84ꢀ6.82 (d, 2H), 6.53 (s, 1H), 3.70 (s, 3H), 2.84ꢀ2.77
(q, 2H), 1.28ꢀ1.25 (t, 3H). 13C NMR (100 MHz) DMSO-d6: 194.3,
162.6, 160.9, 156.1, 154.9, 132.5, 129.5, 125.8, 121.7, 120.3, 115.6, 101.5,
95.7, 56.5, 21.6, 12.2. 1H NMR (400 MHz) CDCl3: 7.79ꢀ7.77 (d, 2H),
7.28ꢀ7.26 (d, 1H), 7.21 (bs, 1H; exchangeable in D2O), 7.02ꢀ7.01 (d,
1H), 6.93ꢀ6.91 (d, 2H), 6.84ꢀ6.81 (dd, 1H), 3.85 (s, 3H), 2.90ꢀ2.84
(q, 2H), 1.33ꢀ1.29 (t, 3H). 13C NMR (100 MHz) CDCl3: 191.5, 165.0,
160.8, 157.9, 154.6, 132.1, 131.5, 121.4, 120.4, 116.0, 115.4, 112.2, 95.8,
55.8, 21.8, 12.4. LC/MS-MS: 297.0 f 121.2 m/z; GS1 and GS2 at 20,
DP = 41, CE = 29, CXP = 6, tR = 4.27 min.
(2-Ethyl-6-hydroxybenzofuran-4-yl)(4-methoxyphenyl)methanone
(34) and (2-Ethyl-6-hydroxybenzofuran-4-yl)(4-hydroxyphenyl)met-
hanone (35). In a RBF/SB (15 mL), 18 (0.200 g, 0.644 mmol) was
diluted with DMF (3.0 mL). To the mixture, NaSEt (0.108 g, 1.29 mmol)
was added, and the contents were heated (110 ( 5 °C, 4.0 h). Additional
NaSEt (0.108 g, 1.29 mmol) was added and heated (14 h). Next, the
reaction was quenched with NH4Cl(aq) and extracted with EtOAc (3 ꢁ
(2-Ethyl-6-methoxybenzofuran-3-yl)(4-hydroxyphenyl)methanone
(30). In a RBF/SB (100 mL), benzofuran (17, 2.00 g, 6.44 mmol) was
diluted with DMF (25 mL). The mixture was stirred while NaSEt (820
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dx.doi.org/10.1021/jm1015022 |J. Med. Chem. 2011, 54, 2701–2713