A. Hashimoto et al. / Bioorg. Med. Chem. 13 (2005) 3627–3639
3635
(235 mg, 2 mmol) in 5 ml of DMF was sparged with
nitrogen for 10min before, 60mg (0.05 mmol) of tetra-
kis(triphenylphosphine) palladium(0) was added. The
reaction mixture was heated at 90 ꢁC for 4 h, then
cooled to room temperature, diluted with methylene
chloride (20ml), and washed with 1 N HCl (10ml),
water (2 · 20ml), brine (20ml), dried over magnesium
sulfate, concentration under reduced pressure, and puri-
fied by silica gel column chromatography (hexane/
magnesium sulfate, and concentration under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc, 8:2) to afford
6
1
(100 mg, 0.3 mmol, 90%). H NMR (400 MHz, CDCl3)
7.06 (s, 2H), 6.98 (s, 1H), 6.68 (s, J = 8.4 Hz, 1H), 6.60
(dd, J = 8.4 Hz and 2.4 Hz, 1H), 4.62 (s, 2H), 4.45 (m,
1H), 3.98 (s, 2H), 3.28 (m, 1H), 2.27 (s, 6H), 1.30(d,
J = 6.0Hz, 6H), 1.17 (d, J = 7.0Hz, 6H); 13C NMR
(100 MHz, CDCl3) 153.24, 138.61, 137.92, 137.61,
137.20, 131.20, 127.01, 126.42, 125.18, 113.04, 70.03,
65.45, 34.43, 27.11, 22.90, 22.41, 20.43; HRMS calcd
for C22H30O2: 326.2246, found: 326.2245.
1
EtOAc, 7:3) to give 275 mg (0.85 mmol, 85%) of 4. H
NMR (400 MHz, CDCl3) 7.34 (s, 2H), 6.90(s, 1H),
6.68 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 8.4, 2.3 Hz, 1H),
4.47 (m, 1H), 4.00 (s, 2H), 3.27 (m, 1H), 2.28 (s, 6H),
1.31 (d, J = 6.0Hz, 6H), 1.16 (d, J = 7.0Hz, 6H); 13C
NMR (100 MHz, CDCl3) 153.56, 143.66, 138.64,
138.21, 133.96, 131.53, 131.50, 129.40, 126.25, 125.08,
119.51, 112.99, 109.85, 69.96, 34.74, 27.08, 22.80,
22.34, 20.24; HRMS calcd for C22H27NO: 321.2093,
found: 321.2092.
5.2.10. 4-(4-Isopropoxy-3-isopropyl-benzyl)-3,5-dimethyl-
benzyl chloride (7). To a solution of 6 (100 mg,
0.3 mmol) in benzene (10 ml) was added thionyl chloride
(0.5 ml, 6.8 mmol). The reaction was heated to reflux for
2 h and the solvent and excess thionyl chloride were
removed by evaporated under reduced pressure. The
product 7 was used to the next step without further puri-
1
5.2.7. 4-(4-Hydroxy-3-isopropyl-benzyl)-3,5-dimethyl-benzo-
nitrile (5). To a solution of 4 (250mg, 0.8 mmol) in
dichloromethane (3 ml) was added anhydrous AlCl3
(140mg, 1.0mmol). The reaction mixture was stirred
at room temperature overnight, diluted with water
(10ml), and extracted with EtOAc (2 · 10ml). The com-
bined organic extract was washed with brine (20ml),
dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography to afford 150mg (80%) of 5. 1H
NMR (400 MHz, CDCl3) 7.33 (s, 2H), 6.86 (s, 1H),
6.59 (dd, J = 8.4, 3.6 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H),
4.60(br s, 1H), 3.97 (s, 2H), 3.13 (m, 1H), 2.25 (s,
6H), 1.18 (d, J = 7.0Hz, 6H); 13C NMR (100 MHz,
CDCl3) 151.35, 143.53, 138.69, 138.18, 131.65, 130.29,
126.35, 125.47, 115.56, 34.77, 27.31, 22.72, 20.30;
HRMS calcd for C19H21NO: 279.1623, found: 279.1620.
fication. H NMR (400 MHz, CDCl3) 7.09 (s, 2H), 6.96
(s, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 8.4,
2.4 Hz, 1H), 4.55 (s, 2H), 4.46 (m, 1H), 3.97 (s, 2H),
3.28 (m, 1H), 2.26 (s, 6H), 1.30(d, J = 6.0Hz, 6H),
1.17 (d, J = 7.0Hz, 6H); 13C NMR (100 MHz, CDCl3)
153.32, 138.21, 137.96, 137.89, 137.83, 135.17, 130.90,
128.47, 126.45, 125.18, 113.01, 70.01, 46.67, 34.47,
27.13, 22.90, 22.43, 20.42; HRMS calcd for C22H29ClO:
344.1907, found: 344.1903.
5.2.11. [4-(4-Isopropoxy-3-isopropyl-benzyl)-3,5-dimethyl-
phenyl]-acetonitrile (8).
A mixture of 7 (100 mg,
0.3 mmol), KCN (66 mg, 10 mmol), and KI (10 mg) in
5 ml of DMF was refluxed for 12 h. After cooling to
room temperature, water (10ml) was added and the
mixture was extracted with ethyl acetate (20ml). The or-
ganic layer was washed with water (2 · 10ml), brine
(10ml), dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by sil-
ica gel column chromatography (hexane/EtOAc, 9:1) to
give 81 mg (0.24 mmol, 81%) of 8. 1H NMR (400 MHz,
CDCl3) 7.00 (s, 2H), 6.93 (s, 1H), 6.67 (d, J = 8.4 Hz,
1H), 6.57 (dd, J = 8.4, 2.4 Hz, 1H), 4.46 (m, 1H), 3.95
(s, 2H), 3.67 (s, 2H), 3.26 (m, 1H), 2.25 (s, 6H), 1.30
(d, J = 6.0Hz, 6H), 1.16 (d, J = 7.0Hz, 6H); 13C
NMR (100 MHz, CDCl3) 153.35, 138.33, 138.00,
137.67, 130.75, 127.68, 127.44, 126.36, 125.13, 118.49,
113.02, 70.01, 34.32, 27.11, 23.33, 22.89, 22.41,
20.39; HRMS calcd for C23H29NO: 335.2249, found:
335.2248.
5.2.8. 4-[2,6-Dimethyl-4-(1H-tetrazol-5-yl)-benzyl]-2-iso-
propyl-phenol (YS-1).
A
mixture of
5
(140mg,
0.5 mmol), sodium azide (1.5 mmol), and triethylamine
hydrochloride (1.5 mmol) in toluene (5 ml) was heated
to reflux for 24 h. After cooling to room temperature,
the product was extracted with water (5 ml). To the
aqueous layer, concentrated HCl was added dropwise
to salt out the product tetrazole YS-1 (140mg, 90%).
1H NMR (400 MHz, CDCl3) 7.92 (s, 1H), 7.31 (s,
1H), 6.88 (s, 1H), 6.68 (dd, J = 8.0, 4.8 Hz, 1H), 6.46
(d, J = 8.4 Hz, 1H), 3.95 (s, 2H), 3.13 (m, 1H), 2.23 (s,
6H), 1.17 (d, J = 7.0Hz, 6H); 13C NMR (100 MHz,
CDCl3) 158.23, 151.64, 141.60, 138.68, 138.47, 131.59,
130.56, 127.29, 126.35, 126.18, 125.40, 115.65, 115.57,
34.63, 27.25, 22.75, 20.27; HRMS calcd for
C19H22N4O: 322.1794, found: 322.1789.
5.2.12. [4-(4-Hydroxy-3-isopropyl-benzyl)-3,5-dimethyl-
phenyl]-acetonitrile (9). The same procedure was
used for removal of isopropyl protecting group as
preparation of compound 5. 1H NMR (400 MHz,
CDCl3) 6.99 (s, 2H), 6.91 (s, 1H), 6.59 (d, J = 8.4 Hz,
1H), 6.52 (d, J = 8.4 Hz, 1H), 4.81 (br s, 1H), 3.94 (s,
2H), 3.68 (s, 2H), 3.15 (m, 1H), 2.23 (s, 6H), 1.20(d,
J = 7.0Hz, 6H); 13C NMR (100 MHz, CDCl3) 151.15,
138.33, 137.53, 134.55, 131.41, 127.71, 127.66, 127.46,
126.37, 125.46, 122.95, 115.40, 34.29, 27.27, 23.33,
22.74, 20.41; HRMS calcd for C20H23NO: 293.1780,
found: 293.1776.
5.2.9. [4-(4-Isopropoxy-3-isopropyl-benzyl)-3,5-dimethyl-
phenyl]-methanol (6). To a solution of 3B (100 mg,
0.3 mmol) in ethanol (5 ml), was added three portions
of NaBH4 (50mg, 1.3 mmol). The mixture was stirred
at room temperature for 1 h before water (10ml) was
slowly added. The mixture was extracted with ethyl ace-
tate (20ml) and the organic layer was washed with 1 N
HCl (10ml), water (2 · 10ml), brine (10ml), dried over