PAPER
Synthesis of Novel Structurally Simplified Estrogen Analogues
2053
2-(4-Ethynyl-3,5-dimethylphenoxy)tetrahydropyran (8h)
UV (MeCN): lmax (log e) = 201.5 (4.4419), 252.5 (4.3170), 287.5
Yield: 95%.
(3.5309), 295.5 nm (3.4683).
IR (film): 3287, 2945, 2875, 2097, 1606, 1477, 1441, 1377, 1356,
1311, 1284, 1260, 1203, 1184, 1147, 1123, 1107, 1078, 1033, 977,
946, 906, 885, 872, 859, 819, 725, 641 cm–1.
2-(4-Ethynyl-3-fluorophenoxy) tetrahydropyran (8k)
Yield: 10%.
IR (KBr): 3298, 2981, 2941, 2872, 2114, 1621, 1566, 1504, 1434,
1393, 1359, 1315, 1285, 1259, 1207, 1187, 1159, 1125, 1097, 1052,
1040, 1023, 978, 948, 906, 872, 856, 823, 810, 756, 665, 610, 585,
540, 474, 442 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53–2.07 (m, 6 H, 3-CH2, 4-CH2,
5-CH2), 3.22 (s, 1 H, 2¢¢-H), 3.62 (dtd, J = 11.3, 3.9, 1.5 Hz, 1 H, 6-
Ha), 3.84 (ddd, J = 11.3, 9.8, 3.0 Hz, 1 H, 6-Hb), 5.41 (t, J = 3.0 Hz,
1 H, 2-H), 6.79 (dd, J = 2.4 Hz, JH-F = 6.8 Hz, 1 H, 2¢-H), 6.82 (dd,
J = 8.8, 2.4 Hz, 1 H, 6¢-H), 7.37 (t, J = JH-F = 8.8 Hz, 1 H, 5¢-H).
13C NMR (75.5 MHz, CDCl3): d = 18.4 (C-4), 25.0 (C-5), 30.0 (C-
3), 62.0 (C-6), 77.2 (C-1¢¢), 80.9 (d, J = 3.3 Hz, C-2¢¢), 96.4 (C-2),
103.3 (d, J = 15.9 Hz, C-4¢), 104.1 (d, J = 24.7 Hz, C-2¢), 112.3 (d,
J = 3.3 Hz, C-6¢), 134.3 (d, J = 4.8 Hz, C-5¢), 158.8 (d, J = 11.1 Hz,
C-1¢), 164.0 (d, J = 252 Hz, C-3¢).
1H NMR (300 MHz, CDCl3): d = 1.52–2.08 (m, 6 H, 3-CH2, 4-CH2,
5-CH2), 2.42 (s, 6 H, 3¢-CH3, 5¢-CH3), 3.42 (s, 1 H, 2¢¢-H), 3.60 (dtd,
J = 11.4, 3.9, 1.5 Hz, 1 H, 6-Ha), 3.87 (ddd, J = 11.4, 9.6, 3.2 Hz, 1
H, 6-Hb), 5.42 (t, J = 3.1 Hz, 1 H, 2-H), 6.75 (s, 2 H, 2¢-H, 6¢-H).
13C NMR (75.5 MHz, CDCl3): d = 18.6 (C-4), 21.2 (3¢-CH3, 5¢-
CH3), 25.2 (C-5), 30.2 (C-3), 61.9 (C-6), 81.3 (C-1¢¢), 83.8 (C-2¢¢),
95.9 (C-2), 114.7 (C-2¢, C-6¢), 115.1 (C-4¢), 142.6 (C-3¢, C-5¢),
156.6 (C-1¢).
MS (EI, 70 eV): m/z (%) = 230.2 (8, [M]+), 146.1 (100, [M –
C5H8O]+), 85.1 (21, [C5H9O]+).
EI-HRMS: m/z calcd for C15H18O2 (230.30): 230.1307; found:
230.1307.
UV (MeCN): lmax (log e) = 212.0 (4.466), 252.5 nm (4.190).
MS (EI, 70 eV): m/z (%) = 220.1 (22, [M]+), 136.1 (26, [M –
C5H8O]+), 107.1 (10, [M – C5H8O – CO – H]+), 85.1 (100,
[C5H9O]+), 67.1 (16, [C5H7]+), 57.1 (19, [C3H5O]+), 41.0 (18,
[C3H5]+).
2-(4-Ethynyl-3-phenylphenoxy)tetrahydro-2H-pyran (8i)
Yield: 92%.
1H NMR (300 MHz, CDCl3): d = 1.56–1.77 (m, 3 H, 4-Ha, 5-CH2),
1.84–1.91 (m, 2 H, 3-CH2), 1.91–2.07 (m, 1 H, 4-Hb), 2.96 (s, 1 H,
4¢-C≡CH), 3.62 (dt, J = 11.4, 1.5, 1 H, 6-Ha), 3.89 (ddd, J = 11.4,
9.6, 3.1 Hz, 1 H, 6-Hb), 5.49 (t, J = 3.1 Hz, 1 H, 2-H), 7.00 (dd,
J = 8.5, 2.5 Hz, 1 H, 6¢-H), 7.07 (d, J = 2.5 Hz, 1 H, 2¢-H), 7.33–
7.47 (m, 3 H, 3¢¢-H, 4¢¢-H, 5¢¢-H), 7.54 (d, J = 8.5 Hz, 1 H, 5¢-H),
7.56–7.63 (m, 2 H, 2¢¢-H, 6¢¢-H).
13C NMR (75.5 MHz, CDCl3): d = 18.6 (C-4), 25.1 (C-5), 30.2 (C-
3), 62.0 (C-6), 78.7 (4¢-C≡CH), 83.1 (4¢-C≡CH), 96.2 (C-2), 113.4
(C-4¢), 115.0 (C-6¢), 117.5 (C-2¢), 127.6 (C-4¢¢), 127.9 (C-2¢¢, C-6¢¢),
129.2 (C-3¢¢, C-5¢¢), 135.2 (C-5¢), 140.2 (C-1¢¢), 145.9 (C-3¢), 157.3
(C-1¢).
EI-HRMS: m/z calcd for C13H13FO2 (220.24): 220.0900; found:
220.0900.
UV (MeCN): lmax (log e) = 202.0 (4.374), 248.5 (4.310), 278.5
(3.422), 282.0 (3.406), 288.0 nm (3.377).
2-[3,5-Dichloro-4-ethynylphenoxy]tetrahydro-2H-pyran (8l)
The reaction was quenched with H2O at –78 °C; yield: 96%.
IR (KBr): 3298, 2949, 2869, 1593, 1543, 1455, 1403, 1359, 1280,
1247, 1202, 1183, 1121, 1058, 1024, 970, 899, 880, 849, 822, 802,
710, 663, 627 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.54–1.78 (m, 3 H, 4-Ha, 5-CH2),
1.80–1.88 (m, 2 H, 3-CH2), 1.88–2.06 (m, 1 H, 4-Hb), 3.57 (s, 1 H,
4¢-C≡CH), 3.63 (dt, J = 11.1, 1.5 Hz, 1 H, 6-Ha), 3.74–3.84 (m, 1 H,
6-Hb), 5.41 (t, J = 2.8 Hz, 1 H, 2-H), 7.06 (s, 2 H, 2¢-H, 6¢-H).
13C NMR (75.5 MHz, CDCl3): d = 18.1 (C-4), 24.9 (C-5), 29.8 (C-
3), 61.9 (C-6), 77.3 (4¢-C≡CH), 85.9 (4¢-C≡CH), 96.5 (C-2), 115.0
(C-4¢), 116.0 (C-2¢, C-6¢), 138.1 (C-3¢, C-5¢), 157.2 (C-1¢).
MS (EI, 70 eV): m/z (%) = 278.1 (15, [M]+), 194.1 (100, [M –
C5H8O]+), 85.0 (28, [C5H9O]+).
ESI-HRMS: m/z calcd for C19H18O2 (278.345): 279.13796 [M +
H]+, 301.11990 [M + Na]+; found: 279.13817 [M + H]+, 301.12005
[M + Na]+.
2-(4-Ethynyl-3-trifluoromethylphenoxy)tetrahydro-2H-pyran
(8j)
Yield: 78%.
MS (EI, 70 eV): m/z (%) = 270.0/272.0 (12/8, [M]+), 186.0/188.0
(12/7, [M – C5H8O]+), 85.0 (100, [C5H9O]+).
IR (KBr): 3255, 2965, 2881, 1613, 1497, 1433, 1328, 1259, 1233,
1206, 1187, 1162, 1118, 1048, 1021, 958, 935, 900, 870, 816, 730,
701, 657, 592, 449 cm–1.
EI-HRMS: m/z calcd for C13H12Cl2O2 (271.139): 270.0214; found:
270.0215.
UV (MeCN): lmax (log e) = 219.5 (4.5833), 256.0 (4.2386), 262.0
1H NMR (300 MHz, CDCl3): d = 1.54–1.79 (m, 3 H, 4-Ha, 5-CH2),
1.83–1.91 (m, 2 H, 3-CH2), 1.91–2.07 (m, 1 H, 4-Hb), 3.26 (s, 1 H,
4¢-C≡CH), 3.62 (dt, J = 11.5, 1.5 Hz, 6-Ha), 3.82 (ddd, J = 11.5,
10.1, 3.1 Hz, 1 H, 6-Hb), 5.48 (t, J = 2.9 Hz, 1 H, 2-H), 7.16 (dd,
J = 8.6, 2.5 Hz, 1 H, 6¢-H), 7.33 (d, J = 2.5 Hz, 1 H, 2¢-H), 7.55 (d,
J = 8.6 Hz, 1 H, 5¢-H).
13C NMR (75.5 MHz, CDCl3): d = 18.3 (C-4), 24.9 (C-5), 30.0 (C-
3), 61.9 (C-6), 79.4 (4¢-C≡CH), 81.1 (4¢-C≡CH), 96.3 (C-2), 112.7
(q, J = 2.2 Hz, C-4¢), 114.5 (q, J = 5.3 Hz, C-2¢), 118.8 (C-6¢),
123.1 (q, J = 274 Hz, 3¢-CF3), 133.4 (q, J = 31 Hz, C-3¢), 136.1 (C-
5¢), 157.0 (C-1¢).
(4.2223), 287.5 (3.0432), 300.0 nm (2.8995).
1-Ethynyl-4-triisopropylsilyloxy-2-triisopropylsilyloxymethyl-
benzene (8m)
Yield: quant.
IR (film): 3315, 2944, 2867, 2104, 1604, 1562, 1489, 1464, 1424,
1384, 1373, 1294, 1238, 1165, 1120, 1067, 1013, 982, 919, 883,
838, 822, 756, 685, 662, 587 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 [d, J = 7.0 Hz, 18 H,
3 × SiCH(CH3)2], 1.10 [d, J = 6.0 Hz, 18 H, 3 × SiCH(CH3)2],
1.13–1.35 [m, 6 H, 6 × SiCH(CH3)2], 3.21 (s, 1 H, 2¢-H), 4.93 (s, 2
H, 1¢¢-CH2), 6.70 (dd, J = 8.3, 2.6 Hz, 1 H, 5-H), 7.19 (d, J = 2.6 Hz,
1 H, 3-H), 7.31 (d, J = 8.3 Hz, 1 H, 6-H).
MS (EI, 70 eV): m/z (%) = 270.1 (13, [M]+), 186.0 (9, [M –
C5H8O]+), 167.0 (6, [M – F – C5H8O]+), 85.0 (100, [C5H9O]+).
EI-HRMS: m/z calcd for C14H13F3O2 (270.247): 270.0868; found:
270.0867.
13C NMR (75.5 MHz, CDCl3): d = 12.0 [4-OSi[CH(CH3)2]3], 12.7
[1¢-OSi[CH(CH3)2]3], 17.9, 18.0 [4-OSi[CH(CH3)2]3, 1¢-
OSi[CH(CH3)2]3], 63.1 (C-1¢¢), 80.7 (C-2 ¢), 81.1 (C-1 ¢), 110.6 (C-
1), 116.9 (C-3), 118.1 (C-5), 133.6 (C-6), 146.0 (C-2), 157.1 (C-4).
Synthesis 2009, No. 12, 2040–2060 © Thieme Stuttgart · New York