1846 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9
J acobs et al.
Hz, 2H, -CH2-COOR); (q, 3J ) 7.1 Hz, 2H, -CH2-CH3); 5.68 (tt,
3J ) 4.4 Hz, 4J ) 0.9 Hz, 1H, H5); 6.95 (d,3J ) 5.3 Hz, 1H,
H3); 7.20 (t, 3J ) 5.3 Hz, 1H, H2); IR (film) (cm-1) 3100, 2880,
2930, 2820, 1735, 1610, 1435, 1330, 1250, 1155, 1030, 870, 650.
Eth yl (7,8-Dih yd r on a p h th a len -5-yl)a ceta te, 8. Prepared
from 3, yield 74% as a colorless oil: bp0.01 115-120 °C; 1H NMR
-OH); 1.50-1.58 (m, 1H, H5); 1.68-1.81 (m, 1H, -CH2-CH2-
OH; 1H, H5); 1.89-1.98 (m, 2H, H6); 2.01-2.10 (m, 1H, -CH2-
CH2-OH); 2.76 (t, 3J ) 5.7 Hz, 2H, H7); 2.85-2.93 (m, 1H, H4);
3.78 (t, J ) 6.6 Hz, 2H, -CH2-OH); 6.86 (d, J ) 5.3 Hz, 1H,
H3); 7.05 (d, 3J ) 5.3 Hz, 1H, H2); IR (film) (cm-1) 3320, 2940,
2860.
3
3
3
(80 MHz, CDCl3) δ 1.19 (t, J ) 7.2 Hz, 3H, -CH3); 2.21-2.41
2-(1,2,3,4-Tetr a h yd r on a p h th a len -1-yl)eth a n ol, 20. Pre-
pared from 12, yield 84% as a colorless oil, pure compound,
checked by TLC: 1H NMR (80 MHz, CDCl3) δ 1.38 (br s, 1H,
-OH); 1.62-2.05 (m, 6H, H2, H3, -CH2-CH2-OH); 2.63-3.04
(m, 3H, H1, H4); 3.76 (t, 3J ) 6.4 Hz, 2H, -CH2-OH); 7.03-
7.15 (m, 4H, Ar-H); IR (film) (cm-1) 3340, 3060, 2940, 2880.
Meth od C. Syn th esis of Eth yl (5,6,7,8-Tetr a h yd r o-
qu in olin -5-yl)a ceta te, 13. Compound 9 (0.78 g, 3.6 mmol)
was dissolved in ethanol (40 mL) and 10% Pd/C (0.1 g) was
added. The reaction mixture was evacuated three times and
then hydrogenated under atmospheric pressure on a shaker
till no more hydrogen was consumed (≈4 h). The catalyst was
filtered off and washed with ethanol. The solvent was removed
under reduced pressure and the residue was purified by bulb
distillation to yield 13 (94%) as a colorless oil: bp0.01 95-100
°C; 1H NMR (80 MHz, CDCl3) δ 1.24 (t, 3J ) 7.2 Hz, 3H, -CH3);
1.71-1.98 (m, 4H, H6, H7); 2.50-2.62 (m, 2H, -CH2-COOR);
2.86-3.46 (m, 3H, H5, H8); 4.16 (q, 3J ) 7.2 Hz, 2H, -CH2-
(m, 2H, H7); 2.68-2.88 (m, 2H, H8); 3.40 (s, 2H, -CH2-COOR);
3
3
4.12 (q, J ) 7.2 Hz, 2H, -CH2-CH3); 5.97 (t, J ) 4.8 Hz, 1H,
H6); 7.08-7.19 (m, 4H, Ar-H).
Meth od B. Syn th esis of 2-(5,6,7,8-Tetr a h yd r oqu in olin -
5-yl)eth a n ol, 21. LiAlH4 (0.8 g, 21.0 mmol) was suspended
in dry ether under a nitrogen atmosphere. A solution of 13
(5.0 g, 23.0 mmol) in dry ether was added dropwise to keep
the reaction mixture slightly boiling. After stirring for 1 h at
room temperature, the suspension was carefully hydrolyzed
with water till no more hydrogen was produced. The solid was
filtered off and washed thoroughly with ether. The filtrate was
dried over Na2SO4 and the solvent was removed under reduced
pressure to yield 21 (89%) as a colorless oil. The crude product
was submitted to the next step without further purification:
1H NMR (80 MHz, CDCl3) δ 1.60-2.08 (m, 6H, H6, H7, -CH2-
CH2-OH); 2.37 (br s, 1H, -OH); 2.85-3.09 (m, 3H, H5, H8);
3.78 (t, 3J ) 6.4 Hz, 2H, -CH2-OH); 7.03 (dd, 3J ) 8.0 Hz, 3J )
3
4
3
3
3
4.8 Hz, 1H, H3); 7.48 (dd, J ) 8.0 Hz, J ) 1.6 Hz, 1H, H4);
CH3); 7.03 (dd, J ) 7.2 Hz, J ) 4.8 Hz, 1H, H3); 7.45 (dd, J
) 7.2 Hz, 4J ) 1.6 Hz, 1H, H4); 8.36 (dd, 3J ) 4.8 Hz, 4J ) 1.6
Hz, 1H, H2).
8.32 (dd, J ) 4.8 Hz, J ) 1.6 Hz, 1H, H2); IR (film) (cm-1
)
3
4
3250, 2920, 2880, 1580.
2-(6,7-Dih yd r oben zo[b]th iop h en -4-yl)eth a n ol, 16. Pre-
pared from 7, yield 95% as a yellow oil, pure compound,
E t h yl (4,5,6,7-Tet r a h yd r ob en zo[b]fu r a n -4-yl)a cet a t e,
10. Prepared from 5, purified by flash chromatography with
CH2Cl2/methanol 50:1, yield 50% as a yellow oil: 1H NMR (400
3
checked by TLC: 1H NMR (400 MHz, CDCl3) δ 2.30 (td, J )
3
3
4
3
4.4 Hz, J ) 8.8 Hz, 2H, H6); 2.48 (td, J ) 7.1 Hz, J ) 4.4
Hz, 2H, -CH2-CH2-OH); 2.74 (t, 3J ) 8.8 Hz, 2H, H7); 3.52 (td,
MHz, CDCl3) δ 1.23 (t, J ) 7.1 Hz, 3H, -CH3); 1.38-1.45 (m,
1H, H5); 1.74-1.80 (m, 1H, H5); 1.91-1.95 (m, 2H, H6); 2.35
3J ) 7.1 Hz, J ) 5.3 Hz, 2H, -CH2-OH); 4.52 (t, J ) 5.3 Hz,
3
3
(dd, 3J ) 8.4 Hz, 2J ) 15.0 Hz, 1H, -CH2-COOR); 2.55-2.60
3
4
3
1H, -OH); 5.55 (tt, J ) 4.4 Hz, J ) 1.3 Hz, 1H, H5); 7.01 (d,
(m, 2H, H7; 1H, -CH2-COOR); 3.10 (m, 1H, H4); 4.17 (q, J )
3J ) 5.3 Hz, 1H, H3); 7.24 (d, J ) 5.3 Hz, 1H, H2); IR (film)
3
3
7.1 Hz, 2H, -CH2-CH3); 6.20 (d, J ) 1.8 Hz, 1H, H3); 7.22 (d,
(cm-1) 3320, 2930, 2880, 2830, 1735.
3J ) 1.8 Hz, 1H, H2); IR (film) (cm-1) 2980, 2940, 2870, 1735,
1450, 1375, 1285, 1250, 1175, 1040, 900, 730.
2-(6,7-Dih ydr o-5H-ben zo[b]fu r an -4-yliden e)eth an ol, 14.
Prepared from 5, yield 76% as a yellow oil, pure compound,
checked by TLC (E/Z mixture). For analytical reasons some E
isomer was separated: 1H NMR (400 MHz, DMSO-d6) δ 1.80
Eth yl (4,5,6,7-Tetr a h yd r oben zo[b]th iop h en -4-yl)a ce-
ta te, 11.24 Prepared from 6 in THF with 2.5-fold excess of Pd/
C, purified by flash chromatography with hexane/ethyl acetate
20:1, yield 66% as a colorless liquid: 1H NMR (400 MHz,
CDCl3) δ 1.27 (t, 3J ) 7.1 Hz, 3H, -CH3); 1.52-1.60 (m, 1H,
H5); 1.74-1.83 (m, 1H, H5); 1.87-2.00 (m, 2H, H6); 2.40 (dd,
3J ) 9.1 Hz, 2J ) 15.0 Hz, 1H, -CH2-COOR); 2.70 (dd, 3J ) 5.3
3
3
(qt, J ) 6.2 Hz, 2H, H6); 2.33 (t, J ) 5.5 Hz, 2H, H5); 2.63
3
3
(t, J ) 6.2 Hz, 2H, H7); 4.08 (t, J ) 6.0 Hz, 2H, -CH2-OH);
4.56 (t, J ) 5.3 Hz, 1H, -OH); 5.64 (t, J ) 6.6 Hz, 1H, -CH-
CH2-OH); 6.61 (d, J ) 1.8 Hz, 1H, H3); 7.45 (d, J ) 1.8 Hz,
1H, H2); IR (film) (cm-1) 3320, 2930, 2860, 2840, 1658, 1522,
1440, 1430, 1335, 1230, 1135, 1000, 900, 750.
3
3
3
3
2
3
Hz, J ) 15.0 Hz, 1H, -CH2-COOR); 2.76 (t, J ) 6.2 Hz, 2H,
H7); 3.22-3.28 (m, 1H, H4); 4.17 (q, 3J ) 7.1 Hz, 2H, -CH2-
CH3); 6.81 (d, J ) 5.3 Hz, 1H, H3); 7.04 (d, J ) 5.3 Hz, 1H,
H2); IR (film) (cm-1) 2980, 2930, 2860, 1738, 1495, 1370, 1280,
1175, 1150, 1032, 875, 732.
3
3
2-(6,7-Dih yd r o-5H -b en zo[b]t h iop h en -4-ylid en e)et h a -
n ol, 15. Prepared from 6, yield 79% as a yellow oil, pure
compound, checked by TLC (E/Z mixture). For analytical
reasons some E isomer was separated: 1H NMR (400 MHz,
DMSO-d6) δ 1.80 (t, 3J ) 6.2 Hz, 2H, H6); 2.37 (t, 2H, H5);
Eth yl (1,2,3,4-Tetr a h yd r on a p h th a len -1-yl)a ceta te, 12.
Prepared from 8, purified by distillation, yield 90% as a yellow
3
3
1
2.77 (t, J ) 6.2 Hz, 2H, H7); 4.11 (t, J ) 5.7 Hz, 2H, -CH2-
oil: bp0.01 95-100 °C (oil bath); H NMR (400 MHz, CDCl3) δ
3
3
1.25 (t, 3J ) 7.2 Hz, 3H, -CH3); 1.69-1.88 (m, 4H, H2, H3);
2.49-2.84 (m, 4H, H4, -CH2-COOR); 3.25-3.43 (m, 1H, H1);
4.17 (q, 3J ) 7.2 Hz, 2H, -CH2-CH3); 7.03-7.15 (m, 4H, Ar-H).
5-[3-(Im id a zol-1-yl)p r op yl]-5,6,7,8-t et r a h yd r oq u in o-
lin e, 51. Prepared from 50, purified by bulb distillation, yield
59% as a yellow oil: bp0.01190 °C; 1H NMR (400 MHz, CDCl3)
δ 1.61-1.93 (m, 8H, H6, H7, -CH2-CH2-CH2-Im); 2.79-2.96
OH); 4.61 (t, J ) 5.3 Hz, 1H, -OH); 5.90 (t, J ) 6.6 Hz, 1H,
3
3
-CH-CH2-OH); 7.22 (d, J ) 5.3 Hz, 1H, H3); 7.24 (d, J ) 5.3
Hz, 1H, H2); IR (film) (cm-1) 3320, 2930, 2860, 2840, 1640.
2-(7,8-Dih yd r oqu in olin -5-yl)eth a n ol, 17. Prepared from
9, yield 80% as a yellow oil, pure compound, checked by TLC:
1H NMR (400 MHz, CDCl3) δ 2.17 (br s, 1H, -OH); 2.25-3.03
(m, 6H, H7, H8, -CH2-CH2-OH); 3.78 (t, 3J ) 6.4 Hz, 2H, -CH2-
3
3
3
3
OH); 5.98 (t, J ) 4.0 Hz, 1H, H6); 7.08 (dd, J ) 8.0 Hz, J )
(m, 3H, H5, H8); 3.97 (t, J ) 7.0 Hz, 2H, -CH2-Im); 6.91 (s,
3
4
3
3
4.8 Hz, 1H, H3); 7.48 (dd, J ) 8.0 Hz, J ) 1.6 Hz, 1H, H4);
1H, H′4); 7.05 (dd, J ) 7.8 Hz, J ) 4.8 Hz, 1H, H3); 7.08 (s,
8.32 (dd, J ) 4.8 Hz, J ) 1.6 Hz, 1H, H2); IR (film) (cm-1
)
3
4
3
4
1H, H′5); 7.34 (dd, J ) 7.8 Hz, J ) 1.5 Hz, 1H, H4); 7.48 (s,
1H, H′2); 8.36 (dd, 3J ) 4.8 Hz, 4J ) 1.5 Hz,1H, H2); IR (KBr)
(cm-1) 3100, 2930, 1570, 1510, 1445, 1230, 1080, 805, 750;
GCMS (70-250 °C, 15 °C/min) >99% pure, tR ) 17.34 min,
(m/z) 241.15 (M+).
3250, 3040, 2920, 2870, 1640, 1570.
2-(4,5,6,7-Tetr ah ydr oben zo[b]fu r an -4-yl)eth an ol, 18. Pre-
pared from 10, yield 91% as a yellow oil, pure compound,
checked by TLC: 1H NMR (400 MHz, CDCl3) δ 1.36-1.49 (m,
1H, H5; 1H, -OH); 1.61-1.78 (m, 1H, H5; 1H, -CH2-CH2-OH);
1.88-1.92 (m, 1H, -CH2-CH2-OH; 2H, H6); 2.57 (t, 3J ) 5.7
Meth od D. Syn th esis of 5-(2-Ch lor oeth yl)-5,6,7,8-tet-
r a h yd r oqu in olin e Hyd r och lor id e, 26. Freshly distilled
SOCl2 (0.43 g, 3.6 mmol) was added dropwise to a solution of
21 (0.35 g, 2.0 mmol) in dry CHCl3 (6 mL) at -8 to 0 °C under
a nitrogen atmosphere. The mixture was slowly warmed and
then refluxed for 2 h. After cooling to room temperature,
solvent and excess thionyl chloride were removed under
reduced pressure to yield 26 (95%) as a beige solid. The crude
3
Hz, 2H, H7); 2.71-2.78 (m, 1H, H4); 3.78 (t, J ) 6.6 Hz, 2H,
3
3
-CH2-OH); 6.26 (d, J ) 1.8 Hz, 1H, H3); 7.24 (d, J ) 1.8 Hz,
1H, H2); IR (film) (cm-1) 3340, 2940, 2860, 1500.
2-(4,5,6,7-Tetr ah ydr oben zo[b]th ioph en -4-yl)eth an ol, 19.
Prepared from 11, yield 95% as a yellow oil, pure compound,
checked by TLC: 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 1H,