3992 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Elhalem et al.
(19:1) as eluent to afford 61 mg (47% yield) of pure compound
16 as a colorless oil: Rf ) 0.55 (hexanes/EtOAc, 7:3); IR (film,
cm-1) 3074, 2926, 2872, 2156, 1589, 1489, 1219, 1032, 758, 692;
1H NMR (CDCl3) δ 3.33 (d, J ) 6.2 Hz, 2 H, PhCH2), 3.36 (t,
J ) 5.9 Hz, 2 H, H-1), 4.30 (t, J ) 5.9 Hz, 2 H, H-2), 5.05 (m,
2 H, CHCH2), 5.95 (ddt, J ) 16.1, 9.5, 6.6 Hz, 1 H, CHCH2),
6.78-7.34 (m, 8 H, aromatic protons); 13C NMR (CDCl3) δ 33.6
(C-1), 34.1 (CHCH2), 66.4 (C-2), 112.7 (C-6′), 116.0 (C-5′), 117.8
(C-2′′), 117.9 (PhCH2), 121.7 (C-3′), 122.6 (C-4′′), 129.6 (C-3′′),
130.9 (C-2′), 136.2 (CHCH2), 150.9 (C-4′), 151.7 (C-1′), 158.2
(C-1′′); MS (m/z, relative intensity) 311 (M+, 100), 271 (21),
225 (18), 185 (21), 132 (81). Anal. (C18H17O2NS) C, H, N, S.
4-P h en oxyp h en yl 4-Tolu en esu lfon a te (18). A solution
of 4-phenoxyphenol (17, 2.000 g, 10.8 mmol) was treated with
tosyl chloride as described for 10. The product was purified
by column chromatography (silica gel), eluting with hexanes/
EtOAc as eluent to afford 3.50 g (95% yield) of pure 18 as a
pale-yellow solid: Rf ) 0.37 (hexanes/EtOAc, 4:1); IR (KBr,
cm-1) 3065, 1595, 1499, 1377, 1260, 1180, 1094, 866.
yield) of pure 25 as a colorless oil: Rf ) 0.62 (hexanes/EtOAc,
7:3); IR (film, cm-1) 3065, 2943, 2874, 1587, 1481, 1140, 1032,
872, 748, 667; MS (m/z, relative intensity) 302 (M+, 5), 300
(M+, 5), 129 (47), 85 (100). Anal. (C13H17O3Br) C, H, Br.
2-Br om op h en oxyeth yla n ol (26). A solution of 25 (628 mg,
2.1 mmol) was treated as described for the preparation of 9.
The product was purified by column chromatography (silica
gel), eluting with hexanes/EtOAc (9:1) as eluent to afford 326
mg (72% yield) of pure 26 as a colorless oil: Rf ) 0.21 (hexanes/
EtOAc, 4:1); IR (film, cm-1) 3383, 3065, 2939, 2876, 1587, 1479,
1248, 1126, 1078, 1055, 1032, 920, 748, 665; MS (m/z, relative
intensity) 218 (M+, 93), 216 (M+, 100), 174 (53), 172 (56).
2-Br om op h en oxyeth yl 4-Tolu en esu lfon a te (27). Alcohol
26 (320 mg, 1.5 mmol) was treated with tosyl chloride (600
mg, 3.1 mmol) as described for 10. The product was purified
by column chromatography (silica gel) using hexanes/EtOAc
(19:1) as eluent to give 402 mg (72% yield) of pure 27 as a
colorless oil: Rf ) 0.19 (hexanes/EtOAc, 4:1); IR (film, cm-1
)
3105, 3059, 2945, 1585, 1485, 1366, 1254, 1175, 937, 669; MS
(m/z, relative intensity) 372 (M+, 1), 370 (M+, 1), 199 (31), 174
(18), 172 (21), 155 (35), 91 (100).
4-P h en oxy-2-(4-tolu en esu lfon yl)p h en ol (19). A solution
of tosylate 18 (1.25 g, 4.4 mmol) was irradiated with a medium-
pressure Hg lamp (TQ 150, Hanau) in a quartz vessel (λexc
:
2-Br om op h en oxyeth yl Th iocya n a te (28). A solution of
27 (358 mg, 0.97 mmol) in dimethylformamide (3 mL) was
treated with potassium thiocyanate (500 mg, 5.2 mmol) as
described for 11. After the usual treatment, the product was
purified by column chromatography (silica gel), eluting with
hexanes/EtOAc (19:1) to give 70 mg (28% yield) of pure
thiocyanate 28 as a colorless oil: Rf ) 0.32 (hexanes/EtOAc,
4:1); IR (film, cm-1) 3065, 2928, 2878, 2156, 1585, 1496, 1279,
1248, 1126, 1032, 750, 665; 1H NMR (CDCl3) δ 3.39 (t, J ) 5.9
Hz, 2 H, H-1), 4.36 (t, J ) 5.9 Hz, 2 H, H-2), 6.91 (m, 2 H,
aromatic protons), 7.28 (dt, J ) 7.6, 1.4 Hz, 1 H, H-5′), 7.56
(dd, J ) 7.7, 1.4 Hz, 1 H, H-3′); 13C NMR (CDCl3) δ 33.2 (C-1),
67.1 (C-2), 111.6 (SCN), 112.7 (C-2′), 114.2 (C-6′), 123.2 (C-
4′), 128.6 (C-5′), 133.7 (C-3′), 154.3 (C-1′); MS (m/z, relative
intensity) 259 (M+, 13), 257 (M+, 13), 178 (9), 86 (100). Anal.
(C9H8ONSBr) C, H, N, S.
254 nm) at room temperature for 7 h. The solvent was
evaporated, and the residue was purified by column chroma-
tography (silica gel), eluting with hexanes/EtOAc (19:1) to yield
972 mg (65% yield) of pure 19 as a white solid: mp 50-52 °C;
Rf ) 0.24 (hexanes/EtOAc, 4:1); IR (KBr, cm-1) 3444, 3059,
1604, 1497, 1213, 1127, 1086, 829, 714, 606, 525; MS (m/z,
relative intensity) 340 (M+, 77), 184 (73), 57 (88), 43 (100).
4-P h en oxy-2-(4-tolu en esu lfon yl)ph en oxyeth yl Tetr ah y-
d r o-2H-p yr a n -2-yl Eth er (20). Compound 19 (635 mg, 2.2
mmol) was treated with bromoethyl tetrahydropyranyl ether
as described for 8. The product was purified by column
chromatography (silica gel), eluting with hexanes/EtOAc (19:
1) to give 440 mg (42% yield) of pure compound 20 as a
colorless oil: HRMS calcd for (C26H28O6S) 468.1607, found
468.1610.
4-P h en oxy-2-(4-tolu en esu lfon yl)p h en oxyeth a n ol (21).
The tetrahydropyranyl group of 20 (220 mg, 0.5 mmol) was
cleaved as described for 9. The product was purified by column
chromatography (silica gel), eluting with hexanes/EtOAc (3:
1) to give 130 mg (68% yield) of pure compound 21 as a white
solid: mp 90 °C; MS (m/z, relative intensity) 384 (M+, 37), 340
(71), 184 (100).
4-P h en oxy-2-(4-tolu en esu lfon yl)p h en oxyeth yl 4-Tolu -
en esu lfon a te (22). Alcohol 21 (140 mg, 0.36 mmol) was
tosylated as described for 10. After the usual workup, 180 mg
(93% yield) of pure 22 was obtained as a white solid: mp 138-
140 °C; Rf ) 0.21 (hexanes/EtOAc, 7:3); IR (KBr, cm-1) 3067,
2986, 2949, 2874, 1597, 1485, 1381, 1315, 1265, 1213, 1180,
1153, 1094, 1026, 920, 773, 662; MS (m/z, relative intensity)
538 (M+, 8), 199 (94), 91 (72), 44 (100).
2-Iod op h en oxyeth yl Tetr a h yd r o-2H-p yr a n -2-yl Eth er
(30). 2-Iodophenol (29, 910 mg, 4.1 mmol) was treated with
bromoethyl tetrahydropyranyl ether as described for 8. The
product was purified by column chromatography (silica gel),
eluting with hexanes/EtOAc (19:1) to afford 940 mg (66% yield)
of pure 30 as a colorless oil: Rf ) 0.61 (hexanes/EtOAc, 4:1);
IR (film, cm-1) 2941, 2870, 1582, 1497, 1439, 1277, 1248, 1138,
1034, 750; 1H NMR (CDCl3) δ 1.53-1.81 (m, 6 H, H-3′′, H-4′′,
H-5′′), 3.55 (m, 1 H, H-6′′a), 3.91 (m, 2 H, H-1), 4.04 (m, 1 H,
H-6′′b), 4.20 (t, J ) 4.8 Hz, 2 H, H-2), 4.82 (distorted t, J ) 3.3
Hz, 1 H, H-2′′), 6.71 (dt, J ) 7.7, 1.2 Hz, 1 H, H-4′), 6.85 (dd,
J ) 8.0, 1.1 Hz, 1 H, H-6′), 7.28 (dt, J ) 7.7, 1.5 Hz, 1 H, H-5′),
7.77 (dd, J ) 7.7, 1.4 Hz, 1 H, H-3′); 13C NMR (CDCl3) δ 19.2
(C-4′′), 25.4 (C-5′′), 30.5 (C-3′′), 62.0 (C-6′′), 66.6 (C-1), 70.4 (C-
2), 86.7 (C-2′), 99.0 (C-2′′), 112.4 (C-6′), 122.6 (C-4′), 129.3 (C-
5′), 139.4 (C-3′), 157.5 (C-1′); MS (m/z, relative intensity) 348
(M+, 6), 246 (3), 220 (4), 129 (37), 85 (100); HRMS calcd for
(C13H17O3I) 348.0222, found 348.0218.
2-Iod op h en oxyeth a n ol (31). Compound 30 (900 mg, 2.6
mmol) was treated with pyridinium 4-toluenesulfonate as
described for the preparation of 9. The product was purified
by column chromatography (silica gel) using a mixture of
hexanes/EtOAc (17:3) as eluent to give 514 mg (75% yield) of
pure 31 as a colorless oil: Rf ) 0.28 (hexanes/EtOAc, 4:1); IR
(film, cm-1) 3383, 2937, 1582, 1474, 1439, 1277, 1248, 1051,
1018, 920, 748, 650; MS (m/z, relative intensity) 264 (M+, 45),
220 (100).
4-P h en oxy-2-(4-tolu en esu lfon yl)p h en oxyeth yl Th iocy-
a n a te (23). Tosylate 22 (90 mg, 0.17 mmol) was treated with
potassium thiocyanate (500 mg, 5.1 mmol) as described for 11.
The product was purified by column chromatography (silica
gel), employing a mixture of toluene/EtOAc (19:1) as eluent
to afford 60 mg (83% yield) of pure 23 as a white solid: mp
118-120 °C; Rf ) 0.25 (hexanes/EtOAc, 7:3); 1H NMR (CDCl3)
δ 2.42 (s, 3 H, Me), 3.23 (t, J ) 6.0 Hz, 2 H, H-1), 4.28 (t, J )
6.0 Hz, 2 H, H-2), 6.90-7.39 (m, 9 H, aromatic protons), 7.78
(d, J ) 8.0 Hz, 2 H, H-2′′′), 7.83 (d, J ) 2.9 Hz, 1 H, H-3′); 13
C
NMR (CDCl3) δ 21.6 (Me), 32.6 (C-1), 68.1 (C-2), 116.2 (C-2′′),
118.5 (C-6′), 120.5 (C-3′), 123.8 (C-4′′), 125.6 (C-5′), 128.0 (C-
2′′′), 129.4 (C-3′′), 130.0 (C-3′′′), 131.4 (C-2′), 138.3 (C-1′′′), 144.4
(C-4′′′), 151.1 (C-4′), 151.6 (C-1′), 156.9 (C-1′′); MS (m/z, relative
intensity) 425 (M+, 43), 340 (33), 232 (11), 184 (66), 139 (82),
119 (100). HRMS calcd for (C22H19O4NS2) 425.0756, found
425.0749.
2-Iod op h en oxyeth yl 4-Tolu en esu lfon a te (32). Alcohol
31 (460 mg, 1.7 mmol) was treated with tosyl chloride
described for 10. Evaporation of the solvent yielded 691 mg
(97% yield) of pure 32 as a colorless oil that was used as such
in the next step: Rf ) 0.32 (hexanes/EtOAc, 4:1); IR (film,
cm-1) 3063, 2953, 2876, 1597, 1495, 1439, 1360, 1250, 1177,
1040, 932, 750; MS (m/z, relative intensity) 418 (M+, 11), 199
(71), 155 (38), 91 (100).
2-Br om oph en oxyeth yl Tetr ah ydr o-2H-pyr an -2-yl Eth er
(25). 2-Bromophenol (24, 865 mg, 5.0 mmol) reacted with
bromoethyl tetrahydropyranyl ether as described for 8. The
product was purified by column chromatography (silica gel),
employing hexanes/EtOAc (19:1) as eluent to give 711 mg (47%
2-Iod op h en oxyeth yl Th iocya n a te (33). Tosylate 32 (309
mg, 0.74 mmol) was treated with potassium thiocyanate as